the MOUSE
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inb4 dnrd n reading without reacting, just skip to end conclusion n leave ur react 
may also be of interest to heightmaxxers @Osie another rlly good thread
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Liver fat is the last place where you want to have excess fat.
The liver, the central hub in our bodies, is key to many metabolic functions.
An astonishing amount of people have liver issues, with fatty liver being the most common. Fatty liver can either be induced by excess alcohol consumption or due to other factors, which is termed non-alcoholic fatty liver disease (NAFLD).
Fatty liver in of itself is relatively harmless, but when it’s packed with the wrong kinds of fats, polyunsaturated fats, it becomes inflamed and progresses to nonalcoholic steatohepatitis (NASH), which can then progress to hepatocellular carcinoma (HCC), which is liver cancer.
Luckily, having a fatty liver doesn’t mean you’ll get liver cancer. Regardless, we want to get the liver lean so that it can function 100%.
The estimated point prevalence of NAFLD in the general Western population is 20–30% and the prevalence of NAFLD rises to 40–70% among patients with type 2 diabetes and up to 90% among patients with morbid obesity (R).
In the elderly, the prevalence rates from NAFLD are around 40.3% and 39.2% among 60–74 and > 74 years old, respectively (R).
An apt description of what the liver does goes as follows (R):
“The liver is the largest gland in the human body. It has an antrophrenic action (both endocrine and exocrine) and more than 150 other functions. In particular, the liver interacts with the glyco-lipid metabolism, being responsible for gluconeogenesis, glycogenolysis, glycogenosynthesis, apolipoprotein synthesis, cholesterol, and triglycerides, and Low-Density Lipoprotein (LDL) cholesterol elimination through biliary route. The bile produced by the liver is also essential for emulsifying lipids in the intestine allowing absorption. The liver is also responsible for maintaining plasma osmolarity, through the production of albumin and globulins, for the production of coagulation factors, such as factor I (fibrinogen), II (thrombin), V, VII, IX, X, XI, and other proteins involved in coagulation processes, such as protein C, protein S, hepcidin, and antithrombin. In addition to these, it also produces other proteins and enzymes essential for survival (e.g., alpha-1 antitrypsin). The liver is also responsible for the catabolism of endogenous toxicants, for the storage of glycogen, vitamin B12, iron and copper, and it mainly contributes to the function of the immune system. For all these reasons, it is evident that liver health is essential for maintenance of the health of the entire organism and must be preserved as much as possible.“
I’ll try to make this article as simple as possible for you while not neglecting the important details. In part 1 I’ll discuss what contributes to fatty liver and what you can do to prevent it. This will be the most comprehensive article on fatty liver you’ll ever lay eyes on, so sticking in there will be totally worth it.
In part 2 I’ll give you a list of a bunch of foods and supplements you can use that have been shown to improve liver function.
Lastly, at the very end of this article, I’ll give you a stack that I would use if I had a fatty liver.
Many things can contribute to fatty liver and some are:
Let’s start at the top.
Fat can come from 3 places. One is the diet, another is from fat stores (adipose tissue) and the other is the conversion of carbohydrates to fat (de novo lipogenesis (DNL)).
Lipolysis is the enzyme that releases fat from fat stores. There is a balance between lipolysis and fat oxidation and glucose oxidation. If you eat glucose your body releases insulin which blocks lipolysis and inhibits fatty acid oxidation.
When the body has stored or burned the glucose, insulin drops and lipolysis increases again. If someone has a fatty liver, they most likely have insulin resistance and their lipolysis is highly upregulated even in the presence of insulin.
“Excess lipolysis results in high free fatty acid (FFA) flux into the liver, where FFAs cause steatosis and exert lipotoxic effects. Triglycerides acid (FFA) flux into the liver, where FFAs cause steatosis and exert lipotoxic effects.” (R)
Not a lot of things inhibit lipolysis, except aspirin, niacin and insulin, so we’ll have to look at factors that promote lipolysis and then inhibit those.
Endotoxins (R), estrogen (R), growth hormone (R), prolactin (R), inflammation (R), gut-derived serotonin (R) and excessive long-duration low-intensity cardio all promote lipolysis. Excess of these will promote insulin resistance and fatty liver.
You can indirectly measure your β-oxidation rate by measuring plasma β-hydroxybutyrate levels as well as the β-hydroxybutyrate to acetoacetate ratio, which is higher in patients with liver disorders (R).
If you’re not yet convinced that excess β-oxidation should be lowered, check out this paper (R):
“500 mg/twice daily of carnitine for 1 year for the treatment for NAFLD showed no significant changes in liver function tests and ultrasound grade.“
A good dose would be 300mg aspirin with each high carb meal to inhibit excess lipolysis and to improve insulin sensitivity.
ATP is created in the electron transport chain (ETC). Carbs, fats and protein are broken down to be used to create NADH and FADH2. NADH and FADH2 donate their hydrogens to complex I and II respectively, where it’s then shuttled to complex III and lastly IV, where water is created, as you can see from the diagram above.
The flow of electrons through these complexes pump hydrogens (H+ in the pic above) out of the mitochondria, creating a membrane potential. These hydrogens re-enter the mitochondria at complex V (ATP synthase), which drives ATP synthesis.
A reduction in ATP contributes to fatty liver and supplementing ATP precursors such as inosine increases ATP and can prevent fatty liver (R, R). (causes of energy defects discussed below)
Alternate electron acceptors, which can help to bypass faulty complexes, such as vitamin C, vitamin K2, methylene blue, beta-lapachone, ubiquinone (CoQ10) and succinic acid, can rescue ATP production.
In this 3 week study, 100mg/day of Coenzyme Q10 supplementation (which increases ATP levels and reduces reactive oxygen species) caused a significant reduction in liver enzymes and inflammatory markers (transaminases, gamma-GT and hsCRP) and degrees of NAFLD, as well as an improvement of the adiponectin/leptin ratio (R).
A simple stack to boost ATP is 10mg vitamin K2 (MK-4), 1g vitamin C, 10mg methylene blue, 500mg inosine and 100mg succinic acid. Add in some B-vitamins and you might just be bouncing off walls at this point.
The drug Remaxol, which contains 5.28g succinate + 0.75g methionine + 2g inosine + 250mg nicotinamide per dose were designed to improve liver function.
But we don’t just want to bypass the ETC (which is what using alternate electron acceptors or donator does), we want to fix it because we don’t want to be on supplements indefinitely. As a side note, most of these compounds don’t just bypass the ETC but actually stimulate the production of new mitochondrial and thus proper functioning electron transport chains.
A major consequence of a faulty ETC is a dramatically greater increase in reactive oxygen species (ROS) production.
Probably the biggest reason for a faulty ETC is due to polyunsaturated fats in the cell membranes. This might be a surprise to many, but omega 3 is actually much more harmful than omega 6. However, omega 6 is still a major issue because the Western diet or standard American diet (SAD; indeed) is choke-full of omega 6 compared to omega 3.
Omega 6 is found in high concentrations in vegetable, seed and nut oils/butters, such as canola, sunflower, safflower, flax, sesame, peanut, almond, cashew, soy, etc.
The safe fats are from animals, such as beef, lamb, buffalo, bison, goat, lean fish and game. Commercially raised poultry and their products are also very high in omega 6.
Your cell membranes reflect the fats you consume in your diet. If you eat a lot of PUFAs, there will be a lot of PUFAs in your cell membranes.
PUFAs are very “flexible” and fluid and that’s exactly what they do to cell membranes as well. This causes the electrons, that flow in the ETC, to leak out. The electrons react with oxygen and create superoxide (O2•- in the diagram below), which then reacts with the PUFAs in the cell membranes, oxidizing them, creating even more toxic radicals called lipid radicals or reactive lipid species (RLS).
Superoxide can also react with nitric oxide and create the highly dangerous and toxic peroxynitrate (a reactive nitrogen species (RNS)), which just absolutely destroys cells.
To sum it up, an excess of PUFAs in the cell membranes causes electrons to leak from the ETC, thus reducing ATP synthesis and creating ROS, RNS and RLS.
These radicals can also oxidize the PUFAs in the cardiolipin (the black dots connected to the ANT in the diagram above. Cardiolipin also stabilizes all the other complexes in the ETC which is not indicated in the diagram above), which stabilizes the complexes in the ETC. Once the cardiolipin is destroyed, it and the complexes exit the cell and trigger cells degradation. The body then senses the cell isn’t functioning properly and is creating an abundance of ROS, and then signals other processes to destroy the cell. This process starts with fission, which removes the damaged part of the cell and then mitophagy clears up the cell fragments.
People with lots of oxidative stress end up with lots of small, toxic mitochondria which doesn’t create enough ATP. Fission goes into overdrive and overwhelms mitophagy and this causes the buildup of too many small toxic cells.
This is where fusion comes in to merge two cells together and rescues the energy deficiency. Then fission can come in and cleaves off the defective part without creating an excess of small “useless” mitochondria. But the thing is, fusion becomes downregulated, and this also contributes to the accumulation of small toxic mitochondria.
To sum it up, fusion is the guy that builds and improves and his partner, fission, is the guy that comes and cleans things up and makes sure everything is working according to plan. Both are necessary, but often there is too little fusion.
Stearic acid and fasting promote mitochondrial fusion and eating food promotes fission. Overeating and lack of fasting can create an excess of fission and too little fusion.
Activation of AMPK and optimal thyroid hormones promotes proper fusion, fission and cell cycles (R).
So our objective to fix cellular function and restore proper ETC function is to lower oxidative stress, promote fusion, activate AMPK and boost thyroid function, which I’ll discuss below.
Sleep apnea, or sleeping with your mouth open, polyunsaturated fats, lipolysis & beta-oxidation, heavy metals, stress, hypothyroidism, parathyroid hormone, pollution, endotoxins, EMF, etc., are all major causes of oxidative stress.
> How to protect yourself against the damages of EMF
A simple front line of defence stack to lower inflammation in the liver is simple to take a combination of copper (I prefer to get it through food and not supplements), glycine (15g+; 5g x3 daily with a meal) and magnesium (200mg x2 to x3 daily) (R).
Loss of sleep, as well as sleep apnea, increases the risk of fatty liver and the progression of liver disease.
Because of the hypoxia and ROS that sleep apnea causes, sleep apnea was found to be significantly correlated with steatosis, lobular inflammation, ballooning degeneration, fibrosis and ALT. The more severe the sleep apnea, the high ALT goes (R).
From this paper (R):
“Intermittent hypoxia (caused by sleep apnea) leads to tissue hypoxia and can result in oxidative stress, mitochondrial dysfunction, inflammation, and overactivation of the sympathetic nervous system, among many other maladaptive effects. In such models, intermittent hypoxia has been shown to cause insulin resistance, dysfunction of key steps in hepatic lipid metabolism, atherosclerosis, and hepatic steatosis and fibrosis, each of which is pertinent to the development and/or progression of NAFLD.“
One way to go about this is to use a CPAP mask or simply tape your mouth shut. I personally think taping your mouth shut is the best way to go about this.
> How to improve your sleep
This one is simple, just reduce your polyunsaturated fat intake. Stick to whole foods and avoid nut (macadamia nuts and coconuts are fine), seed and vegetable oils as well as food prepared with these fats (such as fast food, salad dressing, baked goodies, etc).
PUFAs can produce ROS either by 1) causing electron leak in the ETC, 2) being oxidized themselves by ROS, creating toxins lipid peroxides or 3) being metabolized by the COX and LOX enzymes, creating inflammatory eicosanoids, such as prostaglandins ad leukotrienes.
Aspirin which blocks the COX enzymes, lowers eicosanoid production, thus inhibiting the progression of fatty liver to a much more severe condition, liver steatosis. Observational research (not the best I know) shows that people who take aspirin on a regular basis are less likely to get fatty liver. Additionally, they are also protected against the progression of liver disease from fatty liver to liver steatosis and fibrosis to hepatocellular carcinoma (R, R, R, R).
Vitamin E protects the PUFAs against lipid peroxidation, thus lowering the chance of progressing from NAFLD to NASH and cirrhosis (R). Research also found that people with higher serum vitamin E and C levels are protected against the progression of liver disease (R).
If lipolysis is elevated due to stress, inflammation or endotoxins, it will liberate lots of polyunsaturated fats into the bloodstream, which will just worsen inflammation.
Aspirin can be effectively used to block lipolysis, improve insulin sensitivity and inhibit the conversion of omega 6 to their inflammatory metabolites, prostaglandins.
But lipolysis is not the only guilty factor, but also fatty acid oxidation itself. The breakdown of fat creates much more ROS than the oxidation of glucose, which thereafter induces immune responses in patients with NAFLD (R). Inhibiting β-oxidation will help reduce ROS. Not a lot of things can inhibit β-oxidation, but insulin and Mildronate are very effective.
Thyroid hormones, activation of AMPK and stearic acid can promote fusion and improve energy production.
Stearic acid is found in high amounts in animal fat, such as beef, lamb, goat, buffalo, bison, wild game, cocoa butter and milk and in very low amounts in the fats that are found in PUFA rich sources.
You can also directly supplement stearic acid to bump up your intake. Research shows that stearic acid can potently lower visceral fat (lipolysis is highly upregulated in visceral fat), showing that stearic acid can also help lower excess lipolysis long term. Interestingly, saturated fat release insulin moreso than polyunsaturated fat, which will also help to lower lipolysis.
Not all stearic acid supplements are created equal, so preferable get stearyl alcohol, which is a stearic acid combined with an alcohol molecule. The reason that this is superior is because the stearic acid is a free fatty acid and not a triglyceride, so your body can just absorb it and doesn’t need to break it down.
The stearic acid that is in triglyceride form (which is like every “pure” stearic acid brand out there) will absorb in low amounts because the stearic acid will be solid in your gut and the lipase enzymes will not be able to break it down. The absorption is enhanced if you mix it in a soup or use it in some baked goodie that you’re preparing.
AMPK promotes mitochondrial biogenesis (which is the creation of new mitochondria) and proper fission and fusion, thus lowering ROS.
AMPK promotes include:
Thyroid hormones are essential for energy production and many cellular functions. Thyroid hormones increase the production of new proper functioning mitochondria and this leads to a reduction in ROS and an increase in ATP and CO2.
Fatty liver is much more prevalent in hypothyroidism, compared to normal thyroid function or hyperthyroidism (R). This is because thyroid hormones speed up the utilization of glucose and fat, thus preventing their accumulation.
To boost thyroid hormones, make sure you’re eating enough protein, carb and micronutrients. B-vitamins, iodine, selenium, zinc, iron, etc., are needed for thyroid hormone production and conversion.
Endotoxins are created from gram-negative bacteria in the gut. Endotoxin excess can occur due to an excess of gram-negative bacteria, providing them with too much food and/or having a leaky gut.
Endotoxins promote inflammation, lipogenesis, insulin resistance, cortisol, serotonin, lactate levels, etc., and is very harmful to the body in excess (R).
Endotoxin-stimulated lipolysis can also induce immune responses in patients with NAFLD (R)
“Previous in vitro and in vivo studies have concluded that the imbalance of polarization between M1/M2 phenotypic macrophages will induce chronic inflammation, various infections, systemic allergies, cancer, obesity, and diabetes, as well as NAFLD [84,86]. A promising therapy for NAFLD was recently identified: specific macrophage-targeted treatment. This therapy can help to restrain the polarization of M1 macrophages/Kupffer cells (KCs) and/or induce the protective phenotype of M2 macrophages/KCs [87,88].” (R)
Vitamin E, astaxanthin, curcumin (R), olive leaf extract (R), pregnenolone (R), etc., lower M1 and increase M2 (R), reducing an immune response. Proper glucose oxidation is also essential to prevent M1 polarization (R).
These bacteria are elevated for a reason, so killing them off will not help long term as they will just multiply and take over again. You have to fix the origin, which could be due to hypothyroidism, inadequate stomach acid, inadequate bile acid release, not chewing your food properly, eating too much fibre dense food, stress, parasites, eating inflammatory food, etc.
Antibiotic treatment can markedly lower gut inflammation and leakiness and reduce fatty liver. Combining anti-biotics with a mild uncoupler, such as dietary capsaicin, which significantly increases PPAR-α expression in adipose tissue, can have a synergistic effect at preventing fat accumulation, body fat gain, inflammation and insulin resistance (R).
But not everyone wants to go the antibiotic route and nor is it the best route and this is where natural anti-biotics come in. Things like oregano oil, garlic, clove oil, monolaurin, flowers of sulfur and CamphoSal can do a good job.
To reduce leaky gut, eat less inflammatory foods, reduce excess gut bacteria, reduce PUFA consumption, make sure you’re eating enough copper and use gelatin (bone broth), aloe vera and curcumin (all of which can improve leaky gut).
Quercetin and naringenin act as pre-biotics and change the gut bacteria to a more favourable ratio which will reduce endotoxins, lower TLR4 (the endotoxin receptor), ROS and subsequent liver fat accumulation and liver damage (R, R, R).
TUDCA and taurine can both stimulate the release of bile which can help clean out the gut and detox the body.
Vitamin B2 has also been shown to work great for the gut, modulating it positively.
Cranberry juice exerts anti-endotoxin effects and lowers gut inflammation and subsequent gut serotonin (R, R, R).
Nrf2 or nuclear factor erythroid-2-related factor 2, is pretty impressive as it activates the transcription of over 500 genes in the human genome. Nrf2 and the system that regulates
Nrf2 lower inflammatory responses, improve mitochondrial function and stimulate autophagy, a process by which both toxic protein aggregates and dysfunctional organelles can be degraded.
From this paper (R):
“Nrf2 directly affects the homeostasis of ROS and RNS by regulating the antioxidant defense systems through several mechanisms. These include (a) induction of catabolism of superoxide and peroxides through SOD, Prx (peroxiredoxin), and GPx (glutathione peroxidase); (b) regeneration of oxidized cofactors and proteins, where GSSG is reduced by GSR, Trxox (thioredoxin) by TrxR, and Prx-SO2H by Srx; (c) synthesis of reducing factors, i.e., GSH by GCLC and GCLM, and NADPH by G6PDH and 6PGD; (d ) expression of antioxidant protein Trx and inhibition of expression of Trx inhibitor TXNIP; (e) the increase of redox transport, such as cystine/glutamate transport through xCT; (f) metal-chelation by MT1, MT2, and ferritin; and ( g) induction of stress response proteins, such as HO-1.“
Although the above might seem like a bunch of gobbledygook that makes your brain spin, the point is that Nrf2 has got its’ finger in every pie and is very important for protecting us against oxidative stress.
A few compounds that promote Nrf2 include:
Uncoupling proteins are a family of proteins located in the inner mitochondrial membrane that can dissociate oxidative phosphorylation from respiration, thereby promoting heat production and decreasing oxyradical production.
Meaning, these proteins use the hydrogens that are pumped out of the mitochondria by the electron transport chain to create heat, instead of to drive the synthesis of ATP. This process effectively lower ROS production and the whole subsequent cascade.
A healthy amount of uncoupling is actually very healthy and can promote lifespan.
> How to induce uncoupling
If you get an excess of uncoupling, you can actually die of heat. This is how people die that overdose on the uncoupling drug, DNP.
There are 5 uncoupling proteins. UCP1 mostly lowers ROS and generates heat, whereas UCP2 can reduce or prevent the activation of iNOS, reducing excess NO production. UCP4 can prevent the entry of excess calcium into cells, which also lowers oxidative stress (R).
A specific mitochondrial-targeted uncoupler, DNP-methyl ether (DNPME), is able to prevent lipid accumulation in the liver (R).
The fastest way to induce uncoupling is to use adrenal cortex, thyroid (T4 and T3), progesterone (R) and calcium. No wonder progesterone has the possibility of enhancing life span as it calms the cells and prevents excess intracellular calcium accumulation (excess intracellular calcium is excitatory and promotes ROS and inflammation).
Additional methods include large doses of aspirin (2g per day), methylene blue (10-20mg per day), salt, red meat, lots of glucose with fats and hot spices.
Curcumin (R), wild cabbage, Capsaicin, berberine, caffeine, Allyl-Containing Sulfides in Garlic (R), green tea (R), mint camphor (menthol), cinnamon, Chinese liquorice, Panax ginseng, ellagic acid (found in black raspberries, pomegranates, etc.), bitter orange extract (R), cocoa, etc, etc., also aids in inducing various forms of UCPs.
DNP can also be used but it’s not very safe, whereas Niclosamide appears to be effective and much safer.
Iron is a highly reactive metal, which can increase ROS and induce lipid peroxidation, damaging the liver and speeding up liver disease.
Subjects with higher dietary iron intake have a higher prevalence of NAFLD in a dose-dependent manner (R, R).
Copper, on the other hand, is good for you and aids in regulating iron in the body. Copper improves gut integrity, lowers inflammation and reduces lipogenesis (R).
Pesticides interfere with bodily function and are hepatotoxic (R). Most pesticides, herbicides, fungicides, etc., are also endocrine disruptors.
Number 3 on the list of things to reduce fatty liver and improve liver function is to optimize glucose oxidation. As alluded to earlier, glucose oxidation produces less ROS than fat oxidation, but apart from that, in most cases where things go wrong in the body, glucose oxidation becomes compromised. Endotoxins promote lipolysis, β-oxidation, glycolysis and pyruvate dehydrogenase kinase (PDK), which inhibits PDH (which shuttles pyruvate into the mitochondria). This all leads to a drop in ATP, elevated ROS and lactate and an immune response.
Glycolysis is a very ineffective way of generating ATP, as 1 molecule of glucose produces 2 molecules of ATP through glycolysis, whereas complete breakdown of glucose through oxidative phosphorylation (TCA cycle and ETC) produces 30 molecules of ATP, making it 15 times more effective (R).
The elevated glycolysis and beta-oxidation create a lot of ROS, which, together with lactate, promote lipogenesis and inflammation. Lipogenesis is the creation of fat from carbs. People with fatty liver have elevated lipogenesis and lowering oxidative stress lowers lipogenesis.
An interesting side note, the fat created from glucose and fructose are mainly saturated fat and a little monounsaturated, and these fats, even if they do accumulate in the liver, does not promote inflammation such as PUFAs would as they cannot be oxidized like PUFAs.
If you are not convinced yet that glucose oxidation is absolutely necessary, check this out. Pyruvate dehydrogenase kinase (PDK), the enzyme that inhibits PDH, is highly increased in NASH mice and human patients, which could aggravate hepatic steatosis. Conversely, its deficiency ameliorates the hepatic steatosis significantly in NASH mice by increasing PDH and glucose oxidation (R).
So how do we optimize glucose oxidation?
We inhibit excess lipolysis and block fatty acid oxidation. Free fatty acids (FFAs) inhibit pyruvate dehydrogenase (PDH; transport protein in the pic above), so lowering FFAs with insulin, aspirin or Mildronate will increase PDH.
Sometimes PDH needs a kickstart and magnesium, vitamin B3, B5 and high dose vitamin B1 (600mg+) will do just the job.
Alternatively, pyruvate can enter the mitochondria through pyruvate carboxylase, which uses biotin as a cofactor, so be sure to eat enough biotin, or supplement a small amount.
A neat, yet unconventional supplement that can boost glucose oxidation and inhibit fatty acid oxidation is Pyrucet sold by Idealabs. Be prepared to eat a lot of carbs when taking this supplement!
Lastly, lower endotoxins and inflammation as those increase PDK and inhibit PDH.
People tend to think that carbs (glucose and especially fructose) and insulin are the prime stimulators of lipogenesis.
As you can see from the diagram above, pyruvates enter the mitochondria and then exits again as citrate, which drives lipogenesis.
Lactate, ROS, endotoxin, excess iron, corticotropin-releasing hormone (CRH), prolactin (at least in pigeons) (R), serotonin (R, R), EMF (intracellular calcium promote DNL), ACTH and cortisol excess promotes excess lipogenesis (R, R, R).
But like mentioned earlier, the fat created through lipogenesis does not produce inflammation compared to the unsaturated fats ingested through the diet. AND…malonyl-CoA, created through lipogenesis, inhibits CPT-1, which will lead to a reduction in β-oxidation and ROS and an increase in glucose oxidation.
Quite a few things can lower excess lipogenesis, so check out my other article-specific on that subject for more info on that.
> Why sugar doesn’t make you fat – the ultimate guide on lipogenesis
Now that we’ve discussed all that, let’s look at different methods and supplements that we can use to improve liver function.
All forms of exercise are effective to reduce fat accumulation in the liver, with high-intensity exercise being most effective (R).
Sprints, weight training, swimming, parkour, calisthenics, etc., are all great forms of training.
With old age, the enzyme that creates NAD+ from niacinamide, NAMPT, is reduced and this leads to a drop in NAD+. Animal research shows that mice with reduced NAD+ had moderate NAFLD phenotypes, including lipid accumulation, enhanced oxidative stress, triggered inflammation and impaired insulin sensitivity in the liver.
Putting the animals on a high-fat diet caused even faster deterioration of the liver. Oral administration of a natural NAD+ precursor (they used nicotinamide riboside in the study), completely corrected these NAFLD phenotypes induced by NAD+ deficiency alone or by a high-fat diet (R).
The conclusion of the study states (emphasis mine) (R):
“These results provide the first evidence that ageing-associated NAD(+) deficiency is a critical risk factor for NAFLD, and suggest that supplementation with NAD(+) substrates may be a promising therapeutic strategy to prevent and treat NAFLD.”
NAD+ is rapidly used up on a high-fat diet (R), possibly because the inflammatory fats (PUFAs) causes inflammation and DNA damage, which needs to be fixed by NAD+ dependent enzymes.
A drop in NAD also promotes lipogenesis (R).
I don’t think it’s needed to use nicotinamide riboside (NR) as niacinamide, a much cheaper form of vitamin B3, is just as good at boosting NAD in the liver.
Dietary and supplemental nicotinamide is stored as NAD in the liver (R). High doses of niacinamide might cause liver damage, so supplement methyl donors with it. A 1:1 ratio of betaine with niacinamide might be best.
Gut derived serotonin promotes inflammation and the progression of fatty liver to hepatic steatosis (R). Blocking the enzyme that synthesizes serotonin, tryptophan hydroxylase type I, or blocking the serotonin receptor 5-HT2A, protects the liver against steatosis. Elevated serotonin not only promotes inflammation but also lowers uncoupling protein, promotes lipogenesis and insulin resistance, which can lead to obesity, diabetes and fatty liver (R).
Gut anti-histamines, which block the H2 histamine receptors, are inversely associated with NAFLD (R). This is most likely due to the reduction in serotonin as H2 antagonists lower serotonin (R). If this is the case, then foods high in histamine might also increase serotonin and contribute to related issues.
Histamine, cortisol, endotoxins, parasitic infections and estrogen are inducers of serotonin synthesis. Serotonin is taken up by mast cells, so mast cell degranulation can cause an excess serotonin release. Inhibiting mast cell degranulation with vitamin D, calcium, lemongrass, etc., can help lower excess serotonin.
Activated charcoal, white button mushrooms and bentonite clay can help lower gut serotonin and endotoxins and feverfew, Ginkgo Biloba, Bacopa monneiri blocks 5-HT2A. PUFAs, estrogen and inflammation increase 5-HT2A expression and the chromium in brewers yeast can help to reduce its expression.
Choline and amino acids aid in the transport of fat out of the liver preventing their accumulation. Choline can either be ingested through food or created in the body using amino acids, such as methionine.
Liver phosphatidylcholine is used to build the monolayers of VLDL, and its deficiency increases de novo lipogenesis (R).
A choline deficiency also leads to greater oxidation of cardiolipin, that stabilizes complex I, of the ETC. A drop in complex I activity reduces ATP production and increases ROS production and speeds up the progression of fatty liver (R).
People on a higher protein diet have a lower chance of developing fatty liver, by lowering lipolysis and lipogenesis as well as increasing lipid transport out of the liver (R).
Interestingly sardine protein seems to be an effective protein source, more so than casein, as it lowers oxidative stress and lipid accumulation (R).
Liver supporting herbs and spices work through a variety of mechanisms to promote liver function, reduce fatty liver and lower liver enzymes.
A few mechanisms include activating Nrf2, restoring NAD+, lowering oxidative stress, by increasing catalase and glutathione levels and also scavenging free lipid peroxyl radicals, reducing lipogenesis, improving insulin sensitivity and lowering inflammation.
People with NAFLD are more frequently deficient in vitamin D than in the general population, and the circulating vitamin D levels are proportional to the degree of fibrotic evolution of NAFLD (R).
A vitamin D deficiency would activate Toll-like receptors (the endotoxin receptor), resulting in severe liver inflammation and induction of oxidative stress. Vitamin D supplements could reverse the inflammation caused by NAFLD-related hepatic injury by inhibiting monocyte activation and lowering inflammatory markers such as TNF-α and IL-1 expression (R).
> Vitamin D – the steroid vitamin
Cortisol, the stress hormone, is elevated in individuals with NAFLD (R) and it’s not just a correlation but cortisol directly contributes to fatty liver (R). Cortisol promotes the formation of visceral fat, which is highly lipolytic and releases a lot of fat directly to the liver, causing it to clog up.
The enzyme 11β-hydroxysteroid dehydrogenase 1, which converts the inactive cortisone to the active cortisol is highly expressed in the visceral fat of people with fatty liver (R). Inhibiting it is therapeutic.
Elevated cortisol also contributes to insulin resistance. Blocking it with niacinamide, aspirin, vitamin A, emodin, etc., could help lower liver fat content. Furthermore, lowering/modulating cortisol levels with other adaptogens can also help to lower liver fat and improve insulin sensitivity.
> How to lower cortisol
You’ve made it this far!
If you take anything from this it should be this. A drop in ATP due to mitochondrial dysfunction is at the root of NAFLD. Dysfunction is induced by an excess of oxidative stress and that can be caused by quite a few things, but most importantly, by PUFAs, endotoxins and a reduction in glucose oxidation and thyroid hormones.
Now for the stack that I would use.
First I’d use supplements to improve the electron transport function and increase ATP. Then I’d add in supplements to lower oxidative stress and lastly, throw in a beneficial herb or two.
Stack (can be taken 2-3 times daily):
Quite a stack, but it will be very effective. If you don’t want to go with the shotgun approach, try only one herb (as your stack) at a time and stick to a healthy, fresh, natural diet.
For food, I’d stick with dairy, red meat, organ meat, eggs, bone broth, soups, fruits of all sorts and limit grains, starches and hard to digest veggies, due to the possibility of endotoxin creation.
may also be of interest to heightmaxxers @Osie another rlly good thread
Underrated Factor of HIGH IGF-1 Levels: Liver Function
Introduction: There are many different factors that we’ve come to understand affect our IGF-1 levels. For example, eating in a caloric deficit. However, one thing that’s rarely discussed is liver function and how integral it is to the production of high IGF-1 levels. Today, that is exactly the...
looksmax.org
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Liver fat is the last place where you want to have excess fat.
The liver, the central hub in our bodies, is key to many metabolic functions.
An astonishing amount of people have liver issues, with fatty liver being the most common. Fatty liver can either be induced by excess alcohol consumption or due to other factors, which is termed non-alcoholic fatty liver disease (NAFLD).
Fatty liver in of itself is relatively harmless, but when it’s packed with the wrong kinds of fats, polyunsaturated fats, it becomes inflamed and progresses to nonalcoholic steatohepatitis (NASH), which can then progress to hepatocellular carcinoma (HCC), which is liver cancer.
Luckily, having a fatty liver doesn’t mean you’ll get liver cancer. Regardless, we want to get the liver lean so that it can function 100%.
The estimated point prevalence of NAFLD in the general Western population is 20–30% and the prevalence of NAFLD rises to 40–70% among patients with type 2 diabetes and up to 90% among patients with morbid obesity (R).
In the elderly, the prevalence rates from NAFLD are around 40.3% and 39.2% among 60–74 and > 74 years old, respectively (R).
An apt description of what the liver does goes as follows (R):
“The liver is the largest gland in the human body. It has an antrophrenic action (both endocrine and exocrine) and more than 150 other functions. In particular, the liver interacts with the glyco-lipid metabolism, being responsible for gluconeogenesis, glycogenolysis, glycogenosynthesis, apolipoprotein synthesis, cholesterol, and triglycerides, and Low-Density Lipoprotein (LDL) cholesterol elimination through biliary route. The bile produced by the liver is also essential for emulsifying lipids in the intestine allowing absorption. The liver is also responsible for maintaining plasma osmolarity, through the production of albumin and globulins, for the production of coagulation factors, such as factor I (fibrinogen), II (thrombin), V, VII, IX, X, XI, and other proteins involved in coagulation processes, such as protein C, protein S, hepcidin, and antithrombin. In addition to these, it also produces other proteins and enzymes essential for survival (e.g., alpha-1 antitrypsin). The liver is also responsible for the catabolism of endogenous toxicants, for the storage of glycogen, vitamin B12, iron and copper, and it mainly contributes to the function of the immune system. For all these reasons, it is evident that liver health is essential for maintenance of the health of the entire organism and must be preserved as much as possible.“
I’ll try to make this article as simple as possible for you while not neglecting the important details. In part 1 I’ll discuss what contributes to fatty liver and what you can do to prevent it. This will be the most comprehensive article on fatty liver you’ll ever lay eyes on, so sticking in there will be totally worth it.
In part 2 I’ll give you a list of a bunch of foods and supplements you can use that have been shown to improve liver function.
Lastly, at the very end of this article, I’ll give you a stack that I would use if I had a fatty liver.
Part 1
Many things can contribute to fatty liver and some are:
- an excess of lipolysis and beta-oxidation (the breakdown of fat for energy)
- dysfunctional cellular function
- decreased glucose oxidation
- elevated lipogenesis (the conversion of carbs to fat)
Let’s start at the top.
#1 Inhibit excess lipolysis and beta-oxidation
Fat can come from 3 places. One is the diet, another is from fat stores (adipose tissue) and the other is the conversion of carbohydrates to fat (de novo lipogenesis (DNL)).
Lipolysis is the enzyme that releases fat from fat stores. There is a balance between lipolysis and fat oxidation and glucose oxidation. If you eat glucose your body releases insulin which blocks lipolysis and inhibits fatty acid oxidation.
When the body has stored or burned the glucose, insulin drops and lipolysis increases again. If someone has a fatty liver, they most likely have insulin resistance and their lipolysis is highly upregulated even in the presence of insulin.
“Excess lipolysis results in high free fatty acid (FFA) flux into the liver, where FFAs cause steatosis and exert lipotoxic effects. Triglycerides acid (FFA) flux into the liver, where FFAs cause steatosis and exert lipotoxic effects.” (R)
Not a lot of things inhibit lipolysis, except aspirin, niacin and insulin, so we’ll have to look at factors that promote lipolysis and then inhibit those.
Endotoxins (R), estrogen (R), growth hormone (R), prolactin (R), inflammation (R), gut-derived serotonin (R) and excessive long-duration low-intensity cardio all promote lipolysis. Excess of these will promote insulin resistance and fatty liver.
You can indirectly measure your β-oxidation rate by measuring plasma β-hydroxybutyrate levels as well as the β-hydroxybutyrate to acetoacetate ratio, which is higher in patients with liver disorders (R).
If you’re not yet convinced that excess β-oxidation should be lowered, check out this paper (R):
“500 mg/twice daily of carnitine for 1 year for the treatment for NAFLD showed no significant changes in liver function tests and ultrasound grade.“
A good dose would be 300mg aspirin with each high carb meal to inhibit excess lipolysis and to improve insulin sensitivity.
#2 Fix the electron transport chain
ATP is created in the electron transport chain (ETC). Carbs, fats and protein are broken down to be used to create NADH and FADH2. NADH and FADH2 donate their hydrogens to complex I and II respectively, where it’s then shuttled to complex III and lastly IV, where water is created, as you can see from the diagram above.
The flow of electrons through these complexes pump hydrogens (H+ in the pic above) out of the mitochondria, creating a membrane potential. These hydrogens re-enter the mitochondria at complex V (ATP synthase), which drives ATP synthesis.
A reduction in ATP contributes to fatty liver and supplementing ATP precursors such as inosine increases ATP and can prevent fatty liver (R, R). (causes of energy defects discussed below)
Alternate electron acceptors, which can help to bypass faulty complexes, such as vitamin C, vitamin K2, methylene blue, beta-lapachone, ubiquinone (CoQ10) and succinic acid, can rescue ATP production.
In this 3 week study, 100mg/day of Coenzyme Q10 supplementation (which increases ATP levels and reduces reactive oxygen species) caused a significant reduction in liver enzymes and inflammatory markers (transaminases, gamma-GT and hsCRP) and degrees of NAFLD, as well as an improvement of the adiponectin/leptin ratio (R).
A simple stack to boost ATP is 10mg vitamin K2 (MK-4), 1g vitamin C, 10mg methylene blue, 500mg inosine and 100mg succinic acid. Add in some B-vitamins and you might just be bouncing off walls at this point.
The drug Remaxol, which contains 5.28g succinate + 0.75g methionine + 2g inosine + 250mg nicotinamide per dose were designed to improve liver function.
But we don’t just want to bypass the ETC (which is what using alternate electron acceptors or donator does), we want to fix it because we don’t want to be on supplements indefinitely. As a side note, most of these compounds don’t just bypass the ETC but actually stimulate the production of new mitochondrial and thus proper functioning electron transport chains.
A major consequence of a faulty ETC is a dramatically greater increase in reactive oxygen species (ROS) production.
A. Problems with polyunsaturated fats
Probably the biggest reason for a faulty ETC is due to polyunsaturated fats in the cell membranes. This might be a surprise to many, but omega 3 is actually much more harmful than omega 6. However, omega 6 is still a major issue because the Western diet or standard American diet (SAD; indeed) is choke-full of omega 6 compared to omega 3.
Omega 6 is found in high concentrations in vegetable, seed and nut oils/butters, such as canola, sunflower, safflower, flax, sesame, peanut, almond, cashew, soy, etc.
The safe fats are from animals, such as beef, lamb, buffalo, bison, goat, lean fish and game. Commercially raised poultry and their products are also very high in omega 6.
Your cell membranes reflect the fats you consume in your diet. If you eat a lot of PUFAs, there will be a lot of PUFAs in your cell membranes.
PUFAs are very “flexible” and fluid and that’s exactly what they do to cell membranes as well. This causes the electrons, that flow in the ETC, to leak out. The electrons react with oxygen and create superoxide (O2•- in the diagram below), which then reacts with the PUFAs in the cell membranes, oxidizing them, creating even more toxic radicals called lipid radicals or reactive lipid species (RLS).
Superoxide can also react with nitric oxide and create the highly dangerous and toxic peroxynitrate (a reactive nitrogen species (RNS)), which just absolutely destroys cells.
To sum it up, an excess of PUFAs in the cell membranes causes electrons to leak from the ETC, thus reducing ATP synthesis and creating ROS, RNS and RLS.
These radicals can also oxidize the PUFAs in the cardiolipin (the black dots connected to the ANT in the diagram above. Cardiolipin also stabilizes all the other complexes in the ETC which is not indicated in the diagram above), which stabilizes the complexes in the ETC. Once the cardiolipin is destroyed, it and the complexes exit the cell and trigger cells degradation. The body then senses the cell isn’t functioning properly and is creating an abundance of ROS, and then signals other processes to destroy the cell. This process starts with fission, which removes the damaged part of the cell and then mitophagy clears up the cell fragments.
B. Fission and fusion for cell integrity
People with lots of oxidative stress end up with lots of small, toxic mitochondria which doesn’t create enough ATP. Fission goes into overdrive and overwhelms mitophagy and this causes the buildup of too many small toxic cells.
This is where fusion comes in to merge two cells together and rescues the energy deficiency. Then fission can come in and cleaves off the defective part without creating an excess of small “useless” mitochondria. But the thing is, fusion becomes downregulated, and this also contributes to the accumulation of small toxic mitochondria.
To sum it up, fusion is the guy that builds and improves and his partner, fission, is the guy that comes and cleans things up and makes sure everything is working according to plan. Both are necessary, but often there is too little fusion.
Stearic acid and fasting promote mitochondrial fusion and eating food promotes fission. Overeating and lack of fasting can create an excess of fission and too little fusion.
Activation of AMPK and optimal thyroid hormones promotes proper fusion, fission and cell cycles (R).
So our objective to fix cellular function and restore proper ETC function is to lower oxidative stress, promote fusion, activate AMPK and boost thyroid function, which I’ll discuss below.
C. Lower oxidative stress
Sleep apnea, or sleeping with your mouth open, polyunsaturated fats, lipolysis & beta-oxidation, heavy metals, stress, hypothyroidism, parathyroid hormone, pollution, endotoxins, EMF, etc., are all major causes of oxidative stress.
> How to protect yourself against the damages of EMF
A simple front line of defence stack to lower inflammation in the liver is simple to take a combination of copper (I prefer to get it through food and not supplements), glycine (15g+; 5g x3 daily with a meal) and magnesium (200mg x2 to x3 daily) (R).
I. Sleep apnea
Loss of sleep, as well as sleep apnea, increases the risk of fatty liver and the progression of liver disease.
Because of the hypoxia and ROS that sleep apnea causes, sleep apnea was found to be significantly correlated with steatosis, lobular inflammation, ballooning degeneration, fibrosis and ALT. The more severe the sleep apnea, the high ALT goes (R).
From this paper (R):
“Intermittent hypoxia (caused by sleep apnea) leads to tissue hypoxia and can result in oxidative stress, mitochondrial dysfunction, inflammation, and overactivation of the sympathetic nervous system, among many other maladaptive effects. In such models, intermittent hypoxia has been shown to cause insulin resistance, dysfunction of key steps in hepatic lipid metabolism, atherosclerosis, and hepatic steatosis and fibrosis, each of which is pertinent to the development and/or progression of NAFLD.“
One way to go about this is to use a CPAP mask or simply tape your mouth shut. I personally think taping your mouth shut is the best way to go about this.
> How to improve your sleep
II. Polyunsaturated fats
This one is simple, just reduce your polyunsaturated fat intake. Stick to whole foods and avoid nut (macadamia nuts and coconuts are fine), seed and vegetable oils as well as food prepared with these fats (such as fast food, salad dressing, baked goodies, etc).
PUFAs can produce ROS either by 1) causing electron leak in the ETC, 2) being oxidized themselves by ROS, creating toxins lipid peroxides or 3) being metabolized by the COX and LOX enzymes, creating inflammatory eicosanoids, such as prostaglandins ad leukotrienes.
Aspirin which blocks the COX enzymes, lowers eicosanoid production, thus inhibiting the progression of fatty liver to a much more severe condition, liver steatosis. Observational research (not the best I know) shows that people who take aspirin on a regular basis are less likely to get fatty liver. Additionally, they are also protected against the progression of liver disease from fatty liver to liver steatosis and fibrosis to hepatocellular carcinoma (R, R, R, R).
Vitamin E protects the PUFAs against lipid peroxidation, thus lowering the chance of progressing from NAFLD to NASH and cirrhosis (R). Research also found that people with higher serum vitamin E and C levels are protected against the progression of liver disease (R).
III. Lipolysis & beta-oxidation
If lipolysis is elevated due to stress, inflammation or endotoxins, it will liberate lots of polyunsaturated fats into the bloodstream, which will just worsen inflammation.
Aspirin can be effectively used to block lipolysis, improve insulin sensitivity and inhibit the conversion of omega 6 to their inflammatory metabolites, prostaglandins.
But lipolysis is not the only guilty factor, but also fatty acid oxidation itself. The breakdown of fat creates much more ROS than the oxidation of glucose, which thereafter induces immune responses in patients with NAFLD (R). Inhibiting β-oxidation will help reduce ROS. Not a lot of things can inhibit β-oxidation, but insulin and Mildronate are very effective.
IV. Promote fusion
Thyroid hormones, activation of AMPK and stearic acid can promote fusion and improve energy production.
Stearic acid is found in high amounts in animal fat, such as beef, lamb, goat, buffalo, bison, wild game, cocoa butter and milk and in very low amounts in the fats that are found in PUFA rich sources.
You can also directly supplement stearic acid to bump up your intake. Research shows that stearic acid can potently lower visceral fat (lipolysis is highly upregulated in visceral fat), showing that stearic acid can also help lower excess lipolysis long term. Interestingly, saturated fat release insulin moreso than polyunsaturated fat, which will also help to lower lipolysis.
Not all stearic acid supplements are created equal, so preferable get stearyl alcohol, which is a stearic acid combined with an alcohol molecule. The reason that this is superior is because the stearic acid is a free fatty acid and not a triglyceride, so your body can just absorb it and doesn’t need to break it down.
The stearic acid that is in triglyceride form (which is like every “pure” stearic acid brand out there) will absorb in low amounts because the stearic acid will be solid in your gut and the lipase enzymes will not be able to break it down. The absorption is enhanced if you mix it in a soup or use it in some baked goodie that you’re preparing.
V. Increase AMPK
AMPK promotes mitochondrial biogenesis (which is the creation of new mitochondria) and proper fission and fusion, thus lowering ROS.
AMPK promotes include:
- Milk thistle
- Green tea extract
- Garlic
- Caffeic acid found in coffee (R)
- Ursolic acid
- Ginseng
- Goji berry
- Chlorogenic acid (R)
- Oolong tea (R)
- Leucine (R)
- Naringenin (R)
- Quercetin (R)
- Methylene blue
- Esculetin, a coumarin derivative found in strawberries, black currants, apricots, and cherries (R).
- Berberine (R)
- Celastrol found in Tripterygium wilfordii (Thunder god vine) (R)
- β-hydroxyisovalerylshikonin (β-HIVS), a natural naphthoquinone compound found in Lithospermum erythrorhizon (R).
- Retinoic acid (R)
- Maslinic acid, a compound derived from dry olive-pomace oil which is a byproduct of olive oil extraction (R)
- Licochalcone A found in liquorice root (R)
- Fisetin, found in strawberries, mangoes, cucumber with skin, apples, persimmons, kiwi, peaches, grapes, etc. (R)
- Crocin found in saffron (R)
- Allyl isothiocyanate from black mustard or brown Indian mustard (R)
- Yellow pigments monascin and ankaflavin (R)
- 4-O-methylhonokiol from Magnolia (R)
- Sulforaphane (R)
- Babaodan (R)
- Catalpol found in scullcap (R)
VI. Optimize thyroid
Thyroid hormones are essential for energy production and many cellular functions. Thyroid hormones increase the production of new proper functioning mitochondria and this leads to a reduction in ROS and an increase in ATP and CO2.
Fatty liver is much more prevalent in hypothyroidism, compared to normal thyroid function or hyperthyroidism (R). This is because thyroid hormones speed up the utilization of glucose and fat, thus preventing their accumulation.
To boost thyroid hormones, make sure you’re eating enough protein, carb and micronutrients. B-vitamins, iodine, selenium, zinc, iron, etc., are needed for thyroid hormone production and conversion.
VII. Lower endotoxins
Endotoxins are created from gram-negative bacteria in the gut. Endotoxin excess can occur due to an excess of gram-negative bacteria, providing them with too much food and/or having a leaky gut.
Endotoxins promote inflammation, lipogenesis, insulin resistance, cortisol, serotonin, lactate levels, etc., and is very harmful to the body in excess (R).
Endotoxin-stimulated lipolysis can also induce immune responses in patients with NAFLD (R)
“Previous in vitro and in vivo studies have concluded that the imbalance of polarization between M1/M2 phenotypic macrophages will induce chronic inflammation, various infections, systemic allergies, cancer, obesity, and diabetes, as well as NAFLD [84,86]. A promising therapy for NAFLD was recently identified: specific macrophage-targeted treatment. This therapy can help to restrain the polarization of M1 macrophages/Kupffer cells (KCs) and/or induce the protective phenotype of M2 macrophages/KCs [87,88].” (R)
Vitamin E, astaxanthin, curcumin (R), olive leaf extract (R), pregnenolone (R), etc., lower M1 and increase M2 (R), reducing an immune response. Proper glucose oxidation is also essential to prevent M1 polarization (R).
These bacteria are elevated for a reason, so killing them off will not help long term as they will just multiply and take over again. You have to fix the origin, which could be due to hypothyroidism, inadequate stomach acid, inadequate bile acid release, not chewing your food properly, eating too much fibre dense food, stress, parasites, eating inflammatory food, etc.
Antibiotic treatment can markedly lower gut inflammation and leakiness and reduce fatty liver. Combining anti-biotics with a mild uncoupler, such as dietary capsaicin, which significantly increases PPAR-α expression in adipose tissue, can have a synergistic effect at preventing fat accumulation, body fat gain, inflammation and insulin resistance (R).
But not everyone wants to go the antibiotic route and nor is it the best route and this is where natural anti-biotics come in. Things like oregano oil, garlic, clove oil, monolaurin, flowers of sulfur and CamphoSal can do a good job.
To reduce leaky gut, eat less inflammatory foods, reduce excess gut bacteria, reduce PUFA consumption, make sure you’re eating enough copper and use gelatin (bone broth), aloe vera and curcumin (all of which can improve leaky gut).
Quercetin and naringenin act as pre-biotics and change the gut bacteria to a more favourable ratio which will reduce endotoxins, lower TLR4 (the endotoxin receptor), ROS and subsequent liver fat accumulation and liver damage (R, R, R).
TUDCA and taurine can both stimulate the release of bile which can help clean out the gut and detox the body.
Vitamin B2 has also been shown to work great for the gut, modulating it positively.
Cranberry juice exerts anti-endotoxin effects and lowers gut inflammation and subsequent gut serotonin (R, R, R).
VIII. Modulate NRF2
Nrf2 or nuclear factor erythroid-2-related factor 2, is pretty impressive as it activates the transcription of over 500 genes in the human genome. Nrf2 and the system that regulates
Nrf2 lower inflammatory responses, improve mitochondrial function and stimulate autophagy, a process by which both toxic protein aggregates and dysfunctional organelles can be degraded.
From this paper (R):
“Nrf2 directly affects the homeostasis of ROS and RNS by regulating the antioxidant defense systems through several mechanisms. These include (a) induction of catabolism of superoxide and peroxides through SOD, Prx (peroxiredoxin), and GPx (glutathione peroxidase); (b) regeneration of oxidized cofactors and proteins, where GSSG is reduced by GSR, Trxox (thioredoxin) by TrxR, and Prx-SO2H by Srx; (c) synthesis of reducing factors, i.e., GSH by GCLC and GCLM, and NADPH by G6PDH and 6PGD; (d ) expression of antioxidant protein Trx and inhibition of expression of Trx inhibitor TXNIP; (e) the increase of redox transport, such as cystine/glutamate transport through xCT; (f) metal-chelation by MT1, MT2, and ferritin; and ( g) induction of stress response proteins, such as HO-1.“
Although the above might seem like a bunch of gobbledygook that makes your brain spin, the point is that Nrf2 has got its’ finger in every pie and is very important for protecting us against oxidative stress.
A few compounds that promote Nrf2 include:
- Turmeric
- Cruciferous foods
- Sulfur rich foods
- Quinones
- Anthraquinone found in aloe latex, senna, rhubarb, cascara buckthorn, fungi, lichens, and some insects.
- Naphthoquinone (Vitamin K is a derivative of 1,4-naphthoquinone). Other natural naphtoquinones include juglone (found in black walnut), lapachol (pau d arco tea),
- Benzoquinone. Ubiquinone (CoQ10) is a naturally occurring 1,4-benzoquinone.
- Pyrroloquinoline quinone (PQQ) found in kiwi fruit.
- γ (gamma) and δ (delta) tocopherols
- α-lipoic acid
- Carotenoids
- Olives and olive oil due to being rich in phenolics and terpenoids
- Purple sweet potatoes due to anthocyanin phenolics
- Quercetin
- Apigenin
- Naringenin
- Kaempferol
- Goldenberry extract
- Sulforaphane
- Shikonin, a natural anthraquinone derivative, lowers estrogen by modulates an
estrogen enzyme by down-regulating the expression of steroid sulfatase, essential for estrogen biosynthesis (R, R) - Exercise – obviously it’s not a food unless you’re talking about “exercise snacking” ;D
IX. Induce uncoupling
Uncoupling proteins are a family of proteins located in the inner mitochondrial membrane that can dissociate oxidative phosphorylation from respiration, thereby promoting heat production and decreasing oxyradical production.
Meaning, these proteins use the hydrogens that are pumped out of the mitochondria by the electron transport chain to create heat, instead of to drive the synthesis of ATP. This process effectively lower ROS production and the whole subsequent cascade.
A healthy amount of uncoupling is actually very healthy and can promote lifespan.
> How to induce uncoupling
If you get an excess of uncoupling, you can actually die of heat. This is how people die that overdose on the uncoupling drug, DNP.
There are 5 uncoupling proteins. UCP1 mostly lowers ROS and generates heat, whereas UCP2 can reduce or prevent the activation of iNOS, reducing excess NO production. UCP4 can prevent the entry of excess calcium into cells, which also lowers oxidative stress (R).
A specific mitochondrial-targeted uncoupler, DNP-methyl ether (DNPME), is able to prevent lipid accumulation in the liver (R).
The fastest way to induce uncoupling is to use adrenal cortex, thyroid (T4 and T3), progesterone (R) and calcium. No wonder progesterone has the possibility of enhancing life span as it calms the cells and prevents excess intracellular calcium accumulation (excess intracellular calcium is excitatory and promotes ROS and inflammation).
Additional methods include large doses of aspirin (2g per day), methylene blue (10-20mg per day), salt, red meat, lots of glucose with fats and hot spices.
Curcumin (R), wild cabbage, Capsaicin, berberine, caffeine, Allyl-Containing Sulfides in Garlic (R), green tea (R), mint camphor (menthol), cinnamon, Chinese liquorice, Panax ginseng, ellagic acid (found in black raspberries, pomegranates, etc.), bitter orange extract (R), cocoa, etc, etc., also aids in inducing various forms of UCPs.
DNP can also be used but it’s not very safe, whereas Niclosamide appears to be effective and much safer.
X. Lower excess iron
Iron is a highly reactive metal, which can increase ROS and induce lipid peroxidation, damaging the liver and speeding up liver disease.
Subjects with higher dietary iron intake have a higher prevalence of NAFLD in a dose-dependent manner (R, R).
Copper, on the other hand, is good for you and aids in regulating iron in the body. Copper improves gut integrity, lowers inflammation and reduces lipogenesis (R).
XI. Eat organic
Pesticides interfere with bodily function and are hepatotoxic (R). Most pesticides, herbicides, fungicides, etc., are also endocrine disruptors.
#3 Optimize glucose oxidation
Number 3 on the list of things to reduce fatty liver and improve liver function is to optimize glucose oxidation. As alluded to earlier, glucose oxidation produces less ROS than fat oxidation, but apart from that, in most cases where things go wrong in the body, glucose oxidation becomes compromised. Endotoxins promote lipolysis, β-oxidation, glycolysis and pyruvate dehydrogenase kinase (PDK), which inhibits PDH (which shuttles pyruvate into the mitochondria). This all leads to a drop in ATP, elevated ROS and lactate and an immune response.
Glycolysis is a very ineffective way of generating ATP, as 1 molecule of glucose produces 2 molecules of ATP through glycolysis, whereas complete breakdown of glucose through oxidative phosphorylation (TCA cycle and ETC) produces 30 molecules of ATP, making it 15 times more effective (R).
The elevated glycolysis and beta-oxidation create a lot of ROS, which, together with lactate, promote lipogenesis and inflammation. Lipogenesis is the creation of fat from carbs. People with fatty liver have elevated lipogenesis and lowering oxidative stress lowers lipogenesis.
An interesting side note, the fat created from glucose and fructose are mainly saturated fat and a little monounsaturated, and these fats, even if they do accumulate in the liver, does not promote inflammation such as PUFAs would as they cannot be oxidized like PUFAs.
If you are not convinced yet that glucose oxidation is absolutely necessary, check this out. Pyruvate dehydrogenase kinase (PDK), the enzyme that inhibits PDH, is highly increased in NASH mice and human patients, which could aggravate hepatic steatosis. Conversely, its deficiency ameliorates the hepatic steatosis significantly in NASH mice by increasing PDH and glucose oxidation (R).
So how do we optimize glucose oxidation?
We inhibit excess lipolysis and block fatty acid oxidation. Free fatty acids (FFAs) inhibit pyruvate dehydrogenase (PDH; transport protein in the pic above), so lowering FFAs with insulin, aspirin or Mildronate will increase PDH.
Sometimes PDH needs a kickstart and magnesium, vitamin B3, B5 and high dose vitamin B1 (600mg+) will do just the job.
Alternatively, pyruvate can enter the mitochondria through pyruvate carboxylase, which uses biotin as a cofactor, so be sure to eat enough biotin, or supplement a small amount.
A neat, yet unconventional supplement that can boost glucose oxidation and inhibit fatty acid oxidation is Pyrucet sold by Idealabs. Be prepared to eat a lot of carbs when taking this supplement!
Lastly, lower endotoxins and inflammation as those increase PDK and inhibit PDH.
#4 Decrease lipogenesis
People tend to think that carbs (glucose and especially fructose) and insulin are the prime stimulators of lipogenesis.
As you can see from the diagram above, pyruvates enter the mitochondria and then exits again as citrate, which drives lipogenesis.
Lactate, ROS, endotoxin, excess iron, corticotropin-releasing hormone (CRH), prolactin (at least in pigeons) (R), serotonin (R, R), EMF (intracellular calcium promote DNL), ACTH and cortisol excess promotes excess lipogenesis (R, R, R).
But like mentioned earlier, the fat created through lipogenesis does not produce inflammation compared to the unsaturated fats ingested through the diet. AND…malonyl-CoA, created through lipogenesis, inhibits CPT-1, which will lead to a reduction in β-oxidation and ROS and an increase in glucose oxidation.
Quite a few things can lower excess lipogenesis, so check out my other article-specific on that subject for more info on that.
> Why sugar doesn’t make you fat – the ultimate guide on lipogenesis
Part 2
Now that we’ve discussed all that, let’s look at different methods and supplements that we can use to improve liver function.
#1 Exercise
All forms of exercise are effective to reduce fat accumulation in the liver, with high-intensity exercise being most effective (R).
Sprints, weight training, swimming, parkour, calisthenics, etc., are all great forms of training.
#2 NAD+ precursors
With old age, the enzyme that creates NAD+ from niacinamide, NAMPT, is reduced and this leads to a drop in NAD+. Animal research shows that mice with reduced NAD+ had moderate NAFLD phenotypes, including lipid accumulation, enhanced oxidative stress, triggered inflammation and impaired insulin sensitivity in the liver.
Putting the animals on a high-fat diet caused even faster deterioration of the liver. Oral administration of a natural NAD+ precursor (they used nicotinamide riboside in the study), completely corrected these NAFLD phenotypes induced by NAD+ deficiency alone or by a high-fat diet (R).
The conclusion of the study states (emphasis mine) (R):
“These results provide the first evidence that ageing-associated NAD(+) deficiency is a critical risk factor for NAFLD, and suggest that supplementation with NAD(+) substrates may be a promising therapeutic strategy to prevent and treat NAFLD.”
NAD+ is rapidly used up on a high-fat diet (R), possibly because the inflammatory fats (PUFAs) causes inflammation and DNA damage, which needs to be fixed by NAD+ dependent enzymes.
A drop in NAD also promotes lipogenesis (R).
I don’t think it’s needed to use nicotinamide riboside (NR) as niacinamide, a much cheaper form of vitamin B3, is just as good at boosting NAD in the liver.
Dietary and supplemental nicotinamide is stored as NAD in the liver (R). High doses of niacinamide might cause liver damage, so supplement methyl donors with it. A 1:1 ratio of betaine with niacinamide might be best.
#3 Lower gut serotonin
Gut derived serotonin promotes inflammation and the progression of fatty liver to hepatic steatosis (R). Blocking the enzyme that synthesizes serotonin, tryptophan hydroxylase type I, or blocking the serotonin receptor 5-HT2A, protects the liver against steatosis. Elevated serotonin not only promotes inflammation but also lowers uncoupling protein, promotes lipogenesis and insulin resistance, which can lead to obesity, diabetes and fatty liver (R).
Gut anti-histamines, which block the H2 histamine receptors, are inversely associated with NAFLD (R). This is most likely due to the reduction in serotonin as H2 antagonists lower serotonin (R). If this is the case, then foods high in histamine might also increase serotonin and contribute to related issues.
Histamine, cortisol, endotoxins, parasitic infections and estrogen are inducers of serotonin synthesis. Serotonin is taken up by mast cells, so mast cell degranulation can cause an excess serotonin release. Inhibiting mast cell degranulation with vitamin D, calcium, lemongrass, etc., can help lower excess serotonin.
Activated charcoal, white button mushrooms and bentonite clay can help lower gut serotonin and endotoxins and feverfew, Ginkgo Biloba, Bacopa monneiri blocks 5-HT2A. PUFAs, estrogen and inflammation increase 5-HT2A expression and the chromium in brewers yeast can help to reduce its expression.
#4 Use lipotropic, such as choline and protein
Choline and amino acids aid in the transport of fat out of the liver preventing their accumulation. Choline can either be ingested through food or created in the body using amino acids, such as methionine.
Liver phosphatidylcholine is used to build the monolayers of VLDL, and its deficiency increases de novo lipogenesis (R).
A choline deficiency also leads to greater oxidation of cardiolipin, that stabilizes complex I, of the ETC. A drop in complex I activity reduces ATP production and increases ROS production and speeds up the progression of fatty liver (R).
People on a higher protein diet have a lower chance of developing fatty liver, by lowering lipolysis and lipogenesis as well as increasing lipid transport out of the liver (R).
Interestingly sardine protein seems to be an effective protein source, more so than casein, as it lowers oxidative stress and lipid accumulation (R).
#5 Use liver supportive herbs
Liver supporting herbs and spices work through a variety of mechanisms to promote liver function, reduce fatty liver and lower liver enzymes.
A few mechanisms include activating Nrf2, restoring NAD+, lowering oxidative stress, by increasing catalase and glutathione levels and also scavenging free lipid peroxyl radicals, reducing lipogenesis, improving insulin sensitivity and lowering inflammation.
- Milk thistle (R) – 700mg milk thistle three times daily or 210 mg of silymarin daily.
- “Silymarin is a powerful antioxidant in the cell that can increase catalase and glutathione levels and also scavenge free lipid peroxyl radicals in hepatocytes [6,10,12,17,19,22,25]. Through its antioxidative capabilities, silymarin can restore NAD+ homeostasis, Sirtuin 1 (SIRT1) activity, and the AMP-activated protein kinase α (AMPKα) pathway to improve poly-(ADP-ribose)-polymerase (PARP) function, which protects the cell from the oxidative damage observed in NAFLD [22]. This effect also allows for improved hepatic lipid homeostasis [17,22]. This herb can also reduce hepatic de novo lipogenesis through the downregulation of peroxisome proliferator-activated receptor γ (PPARγ), acetyl-CoA carboxylase (ACC), and fatty acid synthase (FAS) [18]. Furthermore, silymarin can reduce steatosis and insulin resistance seen in NAFLD through restoration of the insulin receptor substrate-1 (IRS-1)/PI3K/Akt pathway [12]. Silymarin is also able to reduce hepatic inflammation through activation of the farnesyl X receptor (FXR) which correlates with the inhibition of NF-κB transactivity“
- Coffee (R) – 5 cups a day or more
- “coffee contains polyphenols similar in structure to silymarin, which can also increase the production of antioxidant proteins [39]. Coffee notably increases periredoxin-1 (PRDX-1) which helps reduce ROS and decrease the oxidative stress in hepatocytes [39]. The synergistic effect of the polyphenols and caffeine in hepatocytes allow it to decrease insulin resistance and steatohepatitis [46]. Moreover, the polyphenols seem to be the cause of the antifibrotic effects of coffee over caffeine.”
- Green tea (EGCG) (R) – 500mg green tea extract daily
- “EGCG decreases hepatic inflammation through the reduction of hepatic cyclooxygenase-2 (COX2), prostaglandin E2, NF-κB, and toll-like receptor 4 (TLR4) [53,56,59]. EGCG also regulates hepatic lipid homeostasis through modulation of mitochondrial complex chain proteins and the previously mentioned AMPK, IRS-1, SREBP, and PPARγ pathways [54,55,60,61]. Furthermore, the polyphenols and EGCG in green tea allow for an antioxidative effect through NADPH oxidase and cytochrome P450 2E1 (CYP2E1)“
- Curcumin (R) – 400-1000mg curcumin daily
- “It acts as an antioxidant through the ability to neutralize free radicals and ROS that lead to oxidative stress in cells via the nuclear factor E2-related factor (Nrf2) and NADPH oxidase [68,74,77,78]. Curcumin can decrease major NAFLD risk factors such as hyperuricemia, dyslipidemia, and insulin resistance through the reduction of serum lipids and uric acid concentration [66]. It can also decrease hepatic steatosis through lipid homeostasis by increasing the inhibition of CD36 and PPARγ by the cAMP response element-binding (CREB) protein and the adiponectin precursor, ADIPOQ [64,72,77]. Curcumin can enhance the expression of PPARα and liver X receptor alpha (LXRα) and reduce SREBP activation and improve lipid balance [76,77]. Hepatic inflammation is controlled by the ability of curcumin to regulate the levels of hepatic proteins NF-κB, IP-10, IL-1β, IFN-γ, TLR4, and CD68 [68]. Also, the impairment intestinal mucosal mechanical barrier typical of NASH is reduced through curcumin’s upregulation of occludin“
- Garlic (R) – 800mg garlic extract daily / garlic essential oil (R)
- “The main active components that give rise to the therapeutic effects of garlic are S-allyl cysteine (SAC), S-allymercaptocysteine (SAMC), diallyl disulfide (DADS), and cinnamoyloctopamines [79,80,81,82,83,84,85,86]. SAC is very similar to resveratrol is its ability to act as a SIRT1 activator that induces the activation of the AMPKα pathway and reduces hepatic lipogenesis and lipotoxicity [79]. It can also prevent lipid induced cell death by reducing free fatty acid ROS production and caspase activation [79]. SAMC and DADS act as antioxidants by inhibiting CYP2E1 and increasing catalase and glutathione peroxidase (GPx) [80,82]. Furthermore, it can decrease fibrosis factors, Transforming Growth Factor-β1 (TGF-β1) and α-Smooth Muscle Actin (α-SMA), and the inflammatory cytokines that would lead to the activation hepatic Kupffer cells and hepatic stellate cells (HSCs) that would cause collagen deposition [80]. Finally, SAMC can reduce inflammation through NF-κB and improve lipid homeostasis and insulin resistance through the AMPK and IRS-1/PI3K/Akt pathway [80,81]. DADS is also able to provide therapeutic effects through the stimulation of PPARα and CPT-1 [82]. The cinnamoyloctopamines are antioxidants that increase superoxide dismutase (SOD) and anti-inflammatory factors by decreasing COX-2“
- Ursolic and carnosic acid (R) – Ursolic acid is found in rosemary, peppermint, basil, lavender, and oregano while carnosic acid is in rosemary and sage
- “Ursolic acid’s ability to improve lipotoxicity and lipid homeostasis comes through regulation of PPARα, the AMPK pathway, and reduction of ER stress in hepatic cells [87,89,90]. Carnosic acid acts through modulation of hepatic SOD, SIRT1, NF-κB, PI3K/Akt, and SREBP-1c to exert antioxidant, anti-inflammatory, anti-adipogenic, and anti-apoptotic effects“
- Ginger – 2g powder daily. Ginger essential oil is effective as well (R)
- “Ginger has antioxidative capabilities through the inhibition of CYP2E1 and upregulation of SOD, catalase, and GPx to reduce ROS and oxidative stress [96] Furthermore, ginger has anti-inflammatory capabilities by reducing cytokines Tumor Necrosis Factor-α (TNF-α), IL-1β, and IL-6, as well as anti-lipotoxic/lipogenic capabilities by reducing SREBP-1c, ACC, and FAS [96].“
- Cocoa powder – 15g+/3tbsp or more per day
- Cinnamon – 1tsp per day or more
- “Similarly, cinnamon has been studied for its antioxidative effects as well and a blinded trial in NAFLD patients by Askari et al. reported that 1500 mg of cinnamon supplementation for 12 weeks reduced AST, ALT, and insulin resistance compared to the placebo group“
- Ginkgo Biloba
- “Through the upregulation of CPT-1A, ginkgo biloba can regulate fatty acid metabolism in the liver and reduce fat accumulation as well as decrease ROS production [103,104]. Furthermore, the ability of Gingko biloba to increase antioxidative enzymes SOD, GPx, and catalase allow it to reduce the oxidative stress in the liver as well“
- Panax ginseng
- “Ginseng is able to reduce lipid accumulation through the induction of the SIRT1/AMPK pathway and activate auto-phagocytic pathways [111,112]. Moreover, ginseng is able to reduce hepatic fibrosis factors such as collagen-1 and α-SMA and prevent HSC activation [113]. Ginseng is able to also reduce inflammation and ER stress through GRP78“
- Lotus
- Goji
- Astragalus & Ciruwujia
- “Astragalus and ciruwujia have yet to be fully explored as therapeutic agents, but regression of fatty liver in NAFLD-induced mouse studies warrant more in-depth understanding [114,121,122,124,126]. Astragalus has hypothesized to function through CPT-1, FXR, PPARα, and SREBP-1c to give its anti-inflammatory and lipid homeostatic effects to improve liver function and steatosis in mice [122,124,126]. Ciruwujia has been postulated to improve liver function through IL-6, CPT-1α, and TLR4 to confer anti-inflammatory effects [114,121].”
- Ashwagandha (R)
- Quzhou Fructus Aurantii (R)
- Picrorhiza kurroa (R)
- Artichoke extract (R)
- Polygonatum kingianum (R)
- “PK also remarkably inhibited the HFD-induced increase of malondialdehyde and the reduction of superoxide dismutase, glutathione peroxidase, ATP synthase, and complex I and II, in mitochondria. Moreover, mRNA expression of carnitine palmitoyl transferase-1 and uncoupling protein-2 was significantly up-regulated and down-regulated after PK treatment, respectively. Finally, PK notably inhibited the HFD-induced increase of caspase 9, caspase 3 and Bax expression in hepatocytes, and the decrease of expression of Bcl-2 in hepatocytes and cytchrome c in mitochondria.
CONCLUSION: PK alleviated HFD-induced NAFLD by promoting mitochondrial functions. Thus, PK may be useful mitochondrial regulators/nutrients to remedy mitochondrial dysfunction and alleviate NAFLD.”
- “PK also remarkably inhibited the HFD-induced increase of malondialdehyde and the reduction of superoxide dismutase, glutathione peroxidase, ATP synthase, and complex I and II, in mitochondria. Moreover, mRNA expression of carnitine palmitoyl transferase-1 and uncoupling protein-2 was significantly up-regulated and down-regulated after PK treatment, respectively. Finally, PK notably inhibited the HFD-induced increase of caspase 9, caspase 3 and Bax expression in hepatocytes, and the decrease of expression of Bcl-2 in hepatocytes and cytchrome c in mitochondria.
- Pomegranate extract (R) – improves mitochondrial function
#6 Liver supportive foods
- Camel milk (R) – 500ml or more per day
- “Camel milk intake for eight weeks decreased hepatic fat accumulation and inflammatory cellular infiltration, preserved liver function, increased the GSH levels and CAT (catalase) activity, decreased the MDA (malondialdehyde) levels, and ameliorated the changes in the lipid profile, AI (atherogenic index), and IR (insulin resistance) in animals from the ChM Group.“
- Cannabinoids (R) – 60-100mg CBD
- “In general, CB1 is pro-fibrogenic, while CB2 is anti-fibrogenic [127,128,129,134]. Tetrahtydrocannabinol (THC) acts via both receptors in a dose-dependent relationship, in which at low-levels it is a CB1 antagonist and has therapeutic effects, but at higher levels becomes a CB1 agonist and becomes a risk factor“
- Sweet cherry (R)
- “beneficially affected lipid metabolism, among others, by regulating the expression of genes associated with fatty acid synthesis and β-oxidation”
- Dragon fruit (R)
- Cerium (it’s a metal, not a food) (R)
- It reduces lipogenesis, ROS, RNS and oxidized cholesterol.
- Saturated fat (R) – MCT oil (R), tallow, cocoa butter, etc.
- “Dietary saturated fat also decreased liver triglyceride, PUFA, and total FFA concentrations (P < 0.05). Increases in dietary saturated fat increased liver membrane resistance to oxidative stress.“
- Low fat diet– less than 10% of your total macros
- It’s a common belief that you have to go on a low carb diet to reduce fatty liver because carbs spike insulin and convert to fat. But research actually shows that both a low carb or low-fat diet is equally effective at lowering liver fat (R). But I’d rather eat a low-fat diet as that way you’ll be able to lower PUFAs much faster and significantly reduce the oxidative potential in the body. Carbs are also anti-stress and full of vitamins and minerals, whereas fats are not.
- Creatine (R) – 5g daily
- Glycine (R) – it decreases inflammation and lowers endotoxins – 5g x3 daily
- Taurine (R) – lowers oxidative stress and inflammation and restores ATP levels – 2g x3 daily
- 7,8-benzoflavone (R) – lowers the aromatase and oxidative stress
- Fruit – pineapple (R), kiwi, mango, olive, papaya, red date, tangerine (R), banana, cherry, fig, lemon, pomegranate, watermelon, berries, grapes, etc (R, R).
- Veggies – asparagus, celery, Chinese chive, cress, dandelion, daylily, summer squash, yam, beets, carrot, collard greens, garlic, onions, leeks, etc (R).
- Eat fresh food only – old, rotten, moldy food are highly toxic and some fungi create highly estrogenic compounds (such as zearalenone), which is harmful to the liver and the rest of the body.
- Avocado oil (R)
- “avocado oil improved the activities of complexes II and III and enhanced the protection conferred by a lipophilic antioxidant against damage by Fe(2+). Avocado oil also decreased ROS generation in Fe(2+)-damaged mitochondria.”
…
“These results suggest that avocado oil improves mitochondrial ETC function by attenuating the deleterious effects of oxidative stress in the liver of diabetic rats independently of a hypoglycemic effect or by modifying the fatty acid composition of mitochondrial membranes.“
- “avocado oil improved the activities of complexes II and III and enhanced the protection conferred by a lipophilic antioxidant against damage by Fe(2+). Avocado oil also decreased ROS generation in Fe(2+)-damaged mitochondria.”
#7 Up your vitamin D
People with NAFLD are more frequently deficient in vitamin D than in the general population, and the circulating vitamin D levels are proportional to the degree of fibrotic evolution of NAFLD (R).
A vitamin D deficiency would activate Toll-like receptors (the endotoxin receptor), resulting in severe liver inflammation and induction of oxidative stress. Vitamin D supplements could reverse the inflammation caused by NAFLD-related hepatic injury by inhibiting monocyte activation and lowering inflammatory markers such as TNF-α and IL-1 expression (R).
> Vitamin D – the steroid vitamin
#8 Lower cortisol
Cortisol, the stress hormone, is elevated in individuals with NAFLD (R) and it’s not just a correlation but cortisol directly contributes to fatty liver (R). Cortisol promotes the formation of visceral fat, which is highly lipolytic and releases a lot of fat directly to the liver, causing it to clog up.
The enzyme 11β-hydroxysteroid dehydrogenase 1, which converts the inactive cortisone to the active cortisol is highly expressed in the visceral fat of people with fatty liver (R). Inhibiting it is therapeutic.
Elevated cortisol also contributes to insulin resistance. Blocking it with niacinamide, aspirin, vitamin A, emodin, etc., could help lower liver fat content. Furthermore, lowering/modulating cortisol levels with other adaptogens can also help to lower liver fat and improve insulin sensitivity.
> How to lower cortisol
Conclusion
You’ve made it this far!
If you take anything from this it should be this. A drop in ATP due to mitochondrial dysfunction is at the root of NAFLD. Dysfunction is induced by an excess of oxidative stress and that can be caused by quite a few things, but most importantly, by PUFAs, endotoxins and a reduction in glucose oxidation and thyroid hormones.
Now for the stack that I would use.
First I’d use supplements to improve the electron transport function and increase ATP. Then I’d add in supplements to lower oxidative stress and lastly, throw in a beneficial herb or two.
Stack (can be taken 2-3 times daily):
- 5mg methylene blue
- 5mg vitamin K2
- 100mg succinic acid
- 1g vitamin C
- 100-400IU vitamin E
- 300mg aspirin
- 5g glycine
- 2g taurine / 400mg TUDCA (use only once daily)
- 2g creatine
- 500mg niacinamide (Niacinamide in the early part of the day and niacin at dinner before bed)
- Herb of choice: milk thistle, Polygonatum kingianum, etc.
Quite a stack, but it will be very effective. If you don’t want to go with the shotgun approach, try only one herb (as your stack) at a time and stick to a healthy, fresh, natural diet.
For food, I’d stick with dairy, red meat, organ meat, eggs, bone broth, soups, fruits of all sorts and limit grains, starches and hard to digest veggies, due to the possibility of endotoxin creation.
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