Fatty Liver: Genetic variants that increase the risk of NAFLD

Non-alcoholic fatty liver disease (NAFLD) is now the leading cause of liver problems worldwide, bypassing alcoholic liver disease. It is estimated that almost half of the population in the US has NAFLD caused by a combination of genetic susceptibility, diet, and lifestyle factors.[ref][ref]

The good news is that fatty liver disease is reversible. Read on for the science details, genetic susceptibility variants, and lifehacks for a healthy liver.

What is NAFLD (non-alcoholic fatty liver disease)?

Normal liver cells (hepatocytes) will store fat in small liposomes or fat storage vesicles. When the liver cells store too much fat, the liposomes grow large and the cells stop functioning as well as normal.

Most people with NAFLD have no symptoms, but some will report fatigue and vague liver pain. NAFLD can cause elevated liver enzymes (AST and ALT), but not everyone with NAFLD has high liver numbers.

Why do we care about fatty liver if it causes few symptoms? Well, a percentage of people with fatty liver will progress to the point of inflammation and fibrosis (called NASH) and then possibly liver failure. Not good…

While the majority of people won’t end up needing a liver transplant, people with fatty liver may end up with metabolic dysfunction (insulin resistance, diabetes), increased inflammation, and liver mitochondrial dysfunction.[ref][ref]

Your liver does a lot! For example, the liver:

• stores glycogen, vitamins, minerals
• produces cholesterol and lipoproteins
• converts glucose into glycogen for stored energy
• creates the enzymes needed for metabolizing toxins and medications
• regulates a bunch of different amino acids
• makes some immune factors and clotting factors
• clears out bilirubin and ammonia
• makes bile for breaking down fats in foods

Everything you eat or drink that gets absorbed in the stomach or intestines first passes through the liver. It’s important, and we all need it to function well for optimal health.

Why does the liver store fat?

Your liver cells always need a source of energy, and stored fat gives the cell continual access to an energy source.

The liver can store fat from the foods that you eat, or it can create fatty acids through de novo lipogenesis, which converts excess carbs into fat. Additionally, the fat liberated from your adipose tissue can be stored in the liver. When the cells need energy, the liver can use up the stored fat via beta-oxidation. Furthermore, VLDL (very low-density lipoprotein) molecules secreted into the bloodstream can export fat from the liver.[ref]

Too much fat coming in (either from excess fatty foods or excess carbohydrates) and not enough fats being exported out (through burning it for energy or exporting as LDL) eventually results in fatty liver disease.

From fatty liver to NASH:

NASH (nonalcoholic steatohepatitis) is the stage of NAFLD when the liver cells are inflamed and there is cell death. At this point, fibrosis may occur in the liver as a way to deal with the death of cells. Advanced fibrosis is known as cirrhosis.[ref]

About 20-30% of patients with NAFLD are likely to progress to NASH[ref]:

 NAFLD –> NASH –> cirrhosis –>liver failure or liver cancer

Causes of fatty liver disease (NAFLD)

While fatty liver isn’t new, the number of people with fatty liver disease has skyrocketed in recent decades. Even kids are getting fatty liver now.[ref] So what is causing all of this liver fat accumulation? It turns out that the answer may be more complex than doctors first thought.

The multiple-hit hypothesis theorizes that for NAFLD to occur you need several insults acting together. This includes “insulin resistance, hormones secreted from the adipose tissue, nutritional factors, gut microbiota, and genetic and epigenetic factors.”[ref]

Is Fatty Liver Hereditary?

Genetic susceptibility can exacerbate dietary and lifestyle factors. NAFLD is considered ‘modestly heritable”, which means that genes play a role, but diet and lifestyle are really important. [ref]

Obesity and insulin resistance can also increase the risk. Genetics can play a role in obesity, as well, but diet and lifestyle are also very important here.

Your gut bacteria (colon and small intestines) can increase the risk for NAFLD.

Excess iron is also linked to fatty liver due to oxidative stress (genetics comes into play here also).[ref]

Dietary causes of NAFLD:

In general, a ‘Western’ diet that includes more processed foods and fewer whole foods is implicated in NAFLD. Excess calories, whether from sugar or fat, are linked with an increased relative risk of fatty liver disease, and if you are overweight, losing some weight – no matter the diet you choose – will likely reduce liver issues. The studies on low carb, low fat, keto, DASH, and Mediterranean diets all show similar benefits on fatty liver.[ref]

Soft drink consumption (containing liquid high fructose corn syrup) in most studies show links to increasing the relative risk of NAFLD (OR=1.29). High red meat consumption also gives a slight increase in the relative risk of NAFLD, while nut consumption shows a slightly decreased risk of fatty liver.[ref]

Fructose as a cause of fatty liver:

Fructose consumption, especially a lot of fructose at one time, increases liver fat. Even short-term high-fructose diets can increase liver fat. A study of healthy adults on a high fructose, iso-caloric diet showed increased liver fat (avg. of 137% increase) after 9 days. The importance of this study is that the participants weren’t consuming more calories, rather just substituting fructose for other foods.[ref]

Why is fructose bad, in comparison to glucose or other carbohydrates? Research shows that dietary fructose increases de novo lipogenesis (creation of fat) while also depleting ATP and increasing mitochondrial ROS. Unlike glucose, fructose does not require insulin for its metabolism.[ref] Is eating an apple or a handful of berries going to cause fatty liver? Probably not, but dumping a bunch of fructose, such as drinking a cola sweetened with high fructose corn syrup, into the liver at one time will cause problems.

Choline is needed:

One dietary component that stands out in NAFLD research is the need for choline.

When researchers want to give mice fatty liver disease, they simply remove choline from the diet. Researchers can also increase fatty liver by knocking out the PEMT (choline related) gene in animals.[ref]

Human trials of choline supplementation (betaine) for NAFLD show mixed results.[ref][ref] On the other hand, increasing phosphatidylcholine may improve fatty liver. Liver biopsies of NAFLD and NASH patients show that their ratio of phosphatidylcholine to phosphatidylethanolamine is altered (low PC).[ref] A phase III clinical trial found a combination of phosphatidylcholine plus silybin to improve liver enzyme and liver histology.[ref]

Whatever diet you choose, from vegan to carnivore, the need for choline still remains. Choline can be made by the body or obtained through diet. Genetics plays a role in how choline is synthesized in the body and metabolized in the liver (read: Choline – an essential nutrient). If you aren’t a champ at converting choline due to genetic variants, getting enough choline from your diet becomes more important.

Which foods are less likely to impact NAFLD?

It’s important to know also what is likely not to impact NAFLD risk significantly…Studies show that the dietary patterns which have no statistical impact on NAFLD include[ref]:

• whole-grain consumption
• refined grain consumption
• fish
• fruit intake
• vegetable intake
• dairy and eggs
• legumes

Beyond what you eat: additional NAFLD causes

It is easy to get a picture in your mind that fatty liver is only found in fat people who are drinking Big Gulps. Diet is important, of course, in fatty liver disease. But it isn’t all about what you eat.  And while obesity is a risk factor for fatty liver, people who are lean can also develop the condition.[ref]

A recent study of NAFLD patients showed that 19% were lean, 52% were overweight, and 29% were obese.[ref] Considering that over 2/3 of adults in the US fall into the overweight or obese category, the percentages given aren’t that far off of the normal distribution. So it is a mistake to think that being normal weight prevents all cases of NAFLD.

In other words, the non-dietary factors in NAFLD are also important.

Circadian Misalignment and NAFLD:

A recent study shows that circadian misalignment, but not sleep duration, increases the relative risk of NAFLD due to metabolic dysfunction by more than 50% (OR=1.67).  Circadian misalignment is defined in this study as falling asleep during the daytime, sleeping before 8 pm, or falling asleep after midnight.[ref]

Why would circadian misalignment increase NAFLD? The circadian clock, the body’s built-in 24-hour rhythms, controls the way that the liver functions at different times of the day. In addition to the body’s core circadian clock, organs such as the liver also have ‘peripheral clocks’ or rhythms based on the time of eating, sleep timing, and exposure to artificial light. For example, the liver creates enzymes needed to break down substances (food, drugs, toxins) at higher levels at times when the enzymes are likely to be needed. Thus, the dysregulation or misalignment of the liver clock causes disruption to the way that the organ functions. This is linked to a number of health problems, including NAFLD.[ref]

Going beyond circadian misalignment, another component of the circadian system, melatonin, may also be important in the pathogenesis of NAFLD. In addition to its role in circadian rhythm, melatonin acts as an antioxidant within cells and helps to maintain mitochondrial function. Animal research shows that supplemental melatonin attenuates NAFLD.[ref][ref] But what about in people?

A recent randomized double-blind, placebo-controlled, clinical trial of 6mg of melatonin nightly 1 hr before bedtime showed that melatonin improves many NAFLD factors. The melatonin group showed statistical significance for decreased liver enzymes, decreased grade of fatty liver, and better metabolic measures.[ref]

SIBO, the gut microbiome, and fatty liver disease:

A number of interesting studies have been done on the link between the gut microbiome and NAFLD. In one study, the gut microbiome of people with genetic obesity was transplanted into germ-free mice. The mice then developed higher levels of liver fat.[ref]

Lipopolysaccharides (LPS), found on the outer membrane of Gram-negative bacteria, increases intestinal permeability. Basically, the body recognizes LPS as being associated with pathogens and mounts an inflammatory response which increases intestinal permeability. Plus, increased intestinal permeability, which can be due to other reasons (e.g. diet), increases the ability of bacteria to translocate from the intestinal microbiome. Animal studies show that LPS directly increases fat in the liver.[ref]

SIBO is an overgrowth of bacteria in the small intestines. A higher prevalence of SIBO is found in people with NAFLD.[ref] Researchers think this could be due to several factors. The increased intestinal permeability (leaky gut) in SIBO patients seems linked with NAFLD, perhaps causing increased inflammation in the liver. Additionally, patients with NASH have altered gut microbiota.[ref]

Bile acids, the gallbladder, and NAFLD:

The liver synthesizes bile acids from cholesterol. After synthesis, the bile acids combine (conjugate) with glycine or taurine and head to the gallbladder for storage until needed. When you eat a meal containing fat, the gallbladder releases the conjugated bile acids to break down the fat for absorption in the intestines. Once in the intestines, these conjugated bile acids de-conjugate and are referred to as secondary bile acids.

People with fatty liver tend to have higher levels of bile acids and a higher ratio of secondary bile acids to conjugated bile acids. In addition to breaking down fats from your food, secondary bile acids also act as messengers that activate bile acid receptors such as TGR5. Additionally, excessive bile acids in the liver cause apoptosis (cell death) of liver cells. The Farnesoid X receptor (FXR) is also activated by bile acids, which regulate the creation of fat in the liver and gluconeogenesis.[ref]

Why all the information about bile acids? I’ll come back to all this in the lifehacks section with possible solutions based on bile acids.

Insulin resistance and fatty liver disease:

Fatty liver, insulin resistance, metabolic syndrome, and diabetes often go together. The research on NAFLD points to a causal link to insulin resistance in the liver.[ref]

Moving from NAFLD to NASH to cirrhosis and/or cancer…

If half the US now has fatty liver, how many of us will end up with cirrhosis or cancer? This is an important question, and researchers are striving to understand the differences in genetics and diet that can lead to NAFLD progressing.

A recent metabolomics (small molecules or metabolites) study looked into the differences in fibrosis in people with NAFLD-HCC. The study showed that higher levels of choline derivatives and glutamine were present in people without liver fibrosis, while people with liver fibrosis had a decrease in monounsaturated fats, an increase in saturated fats, and an accumulation of branched amino acids.[ref]

Alcohol and fatty liver disease:

Since I’ve touched on a variety of NAFLD causes, let’s talk about how alcohol also increases liver fat also.

When you drink the occasional alcoholic drink or two, most of the alcohol breaks down (metabolized) via that alcohol dehydrogenase enzyme. But when you consume a lot of alcohol or chronically consume excess alcohol, more and more of the ethanol’s metabolism uses another enzyme called CYP2E1.

The CYP2E1 enzyme is elevated in people with either alcohol or non-alcohol induced fatty liver. The elevated CYP2E1 enzyme also has links to insulin resistance and the progression of NAFLD to NASH.[ref]

When alcohol metabolism uses the CYP2E1 enzyme, a reduction occurs in NAD+ and the inhibition of beta-oxidation (using fat for fuel) in the liver cells. Additionally, the breakdown products of alcohol impair the secretion of fatty acids from the liver via VLDL. So you have the double-whammy of not secreting fat and also not burning fat, resulting in a buildup of fat in the liver. Circadian rhythm also comes into play here, with alcohol altering circadian clock genes. Finally, alcohol consumption alters the gut microbiome and intestinal permeability.[ref][ref]

Genetic variants that increase fatty liver risk:

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Note that several studies show that the effects of these first two risk factors are additive.[ref] This means that having both of the first two variants increases your risk more than just having one of them.

PNPLA3 gene: patatin-like phospholipase-3 enzyme, strongly linked in genetic studies to a significant increase in the risk for NAFLD. This enzyme interacts with the retinol form of vitamin A.

TM6SF2 gene: transmembrane 6 superfamily member 2 also has links to a significant increase in NAFLD in numerous studies. This protein is important in stabilizing APOB, which is an apolipoprotein that carries VLDL from the liver (among other particles)[ref]

HSD17B13 gene: hydroxysteroid 17β-dehydrogenase 13 enzyme; the function isn’t really known but it plays a role in lipid droplet formation in the liver.[ref]

MBOAT7 gene: codes for a protein that incorporates arachidonic acid into phosphatidylinositol.

GCKR gene: glucokinase regulatory protein. The variant below increases glucose uptake by liver cells and increases lipid accumulation.[ref]

CYP2E1 gene: codes for an enzyme important in ethanol metabolism

HFE gene: regulates iron absorption in the intestines, mutations can lead to hemochromatosis

PEMT gene: phosphatidylethanolamine N-methyltransferase enzyme that helps convert phosphatidylethanolamine to phosphatidylcholine.

NCAN gene: encodes the neurocan core protein

Genetic variants impacting NAFLD progression:

Several genetic variants impact how quickly (or whether) fatty liver will progress to the point of inflammation, cell death, and fibrosis (NASH).

SERPINA1 gene: carriers of mutations in this gene are at risk for alpha-1 antitrypsin deficiency.

SOD2 gene: increased fatty acid oxidation causes an increase in ROS.

IFNL3 (IL28B) gene:  interferon-lambda-3, an interferon important in viral infections such as hepatitis C

Lifehacks:

Figure out if you have fatty liver:

If you are obese and have diabetes, it is likely that you have fatty liver. But what if you are of normal weight, or if you are overweight but have no problem with insulin resistance? You would need to get an ultrasound from your doctor to know if you have fatty liver. Waiting for your liver enzymes to be elevated or for your liver to start hurting is not a good plan.

If you carry the genetic risk factors for NAFLD, it is a good idea to prioritize diet and liver health – whether to reverse your current fatty liver disease or to prevent it from happening.

Diet and lifestyle:

What you eat and how much you eat matters in NAFLD. Cut out the junk food, avoid sodas, and eat a whole foods diet… This is the low-hanging fruit, the first place to start.

Losing weight, if you are overweight, should help to reduce fatty liver disease. The type of diet doesn’t seem to make much of a difference — so choose a diet that you can stick to long-term and that fits with your family and lifestyle.[ref][ref]

Keep in mind, though, that choline is important in reversing fatty liver, so ensure that you are getting plenty of choline in whatever diet you choose. Foods high in choline include liver, eggs, steak, chicken, and fish. If you’re on a vegetarian diet, it is a bit more difficult to meet your need for choline. Soybeans, potatoes, beans, and quinoa have some choline in them.

Obviously, people who are of normal weight can also have fatty liver disease, and an overall healthy diet that contains choline will is still important.

Keeping your gut microbiome healthy (e.g. eating vegetables with fiber) and preventing leaky gut may also help normalize liver fat.

Circadian rhythm is important in the development of NAFLD. Thus, getting your circadian rhythm on track through consistent sleep timing, eating during the daytime, and blocking blue light at night to increase melatonin production.

Specific dietary interactions with genetic variants:

Watch your alcohol consumption, perhaps especially if you carry the CYP2E1 genetic variant. While this may be something that a lot of people don’t want to hear, if you are drinking each night (especially in combination with other dietary factors), you are likely increasing the risk of fatty liver. Most people who drink more than 3 alcoholic drinks (>40g alcohol) per day will develop fatty liver, but more moderate, regular drinking can also add to the liver’s burden.[ref]

The PNPLA3 gene interacts with vitamin A in the retinol forms and its expression is regulated by both insulin and retinol availability.[ref]  Vitamin A in the retinol form is a fat-soluble vitamin that is regulated and stored by the liver. NAFLD and liver disease can lead to vitamin A deficiency.[ref] Beta-carotene, from plant sources, is the main form of vitamin A in many people’s diets, but not everyone converts beta-carotene to vitamin A very well (check your genes here). Vitamin A is dysregulated in fatty liver disease.[ref] I’m honestly not sure if taking higher doses of retinyl palmitate is a good idea or not, since the damaged cells may not be able to store and regulate it appropriately. Talk to your doctor, or stick with the safer option of getting your vitamin A from foods or lower doses of supplements.

Foods high in the retinol form of vitamin A include liver (beef, lamb, chicken, etc), salmon, mackerel, pasture-raised eggs, and grass-fed dairy such as whole milk and butter. Liver really is a great source of vitamin A, and there are a variety of recipes for sneaking some liver into your diet if you hate the taste of liver as much as I do.

People with the PNPLA3 variant also have significantly higher polyunsaturated fatty acid (PUFA) levels in their liver fat. Recent research shows that the variant causes increased liver retention of dietary PUFA.[ref] The ‘western’ diet has shifted in the last few decades to having a higher percentage of PUFA than monounsaturated (MUFA) or saturated fatty acids (SFA). The biggest source of polyunsaturated fatty acids in the diet are fried foods — usually fried in some kind of seed oil (corn, canola, soybean). Additionally, sauces such as mayo and salad dressings almost always contain PUFA.

The GCKR variant increases the uptake of glucose in the cells of the liver. This leads to decreased use of fat by the liver cells (beta-oxidation) and an increase in the accumulation of lipids.[ref] Cutting out sugar is likely beneficial to everyone with fatty liver disease, but it may be most important for people with the GCKR variant.

Inositol? The MBOAT7 gene involves the creation of phosphatidylinositol. Inositol production occurs in the body or available in foods and supplements. Inositols are used in many different physiological functions and decreased inositol is implicated in insulin resistance.  People with NAFLD are more likely to have low inositol levels, and inositol supplementation reverses fatty liver in animal studies. There aren’t a lot of human studies, though, and the one randomized controlled trial didn’t show much of a result.[ref] Myo-inositol is available as a supplement and often recommended for people with PCOS (which is also linked to insulin resistance).

Supplements for NAFLD:

(Check with your doctor before beginning supplements if you have any questions or medication interactions.)

Melatonin: A randomized controlled trial of 6mg/night showed efficacy in reducing liver enzymes and liver fat in people with NAFLD.[ref]

TUDCA – conjugated bile acid supplement:  TUDCA, tauroursodeoxycholic acid, is a taurine conjugated bile acid supplement available over-the-counter. In animal studies, it attenuates fatty liver, inflammation, and insulin resistance in mice. It also increases tight junctions in the intestines.[ref] A clinical trial in obese men found that TUDCA increased insulin sensitivity in the liver and muscle by 30%.[ref] TUDCA or UDCA, which is the bile acid without taurine, are often used to treat primary biliary cholangitis, which is an autoimmune form of liver inflammation. A clinical trial for primary biliary cholangitis showed that 250mg of TUDCA 3 times per day was effective for reducing liver enzymes (ALP) by more than 25% in about a quarter of study participants. The study lasted six months and showed that TUDCA was well tolerated.[ref]

Probiotics: A randomized placebo-controlled trial showed that the fatty liver index (FLI) decreased in diabetic subjects taking a probiotic blend (14 strains of Bifidobacterium, Lactobacillus, Lactococcus, and Propionibacterium). The FLI for the probiotic group decreased from 84 to 79 after 8 weeks of supplementation. The placebo group showed no reduction.[ref]

Reducing oxidative stress in the liver cells:

Berberine: A randomized controlled trial looked at the effects of lifestyle intervention vs. berberine plus lifestyle intervention. Adding berberine (500mg, 3x per day) resulted in a more significant decrease in liver fat along with a greater decrease in weight, HOMAR-IR, and lipid profiles.[ref]

Quercetin: Animal studies show that quercetin reduces NAFLD and decreases insulin resistance through modulating gene expression of CYP2E1 and through changes to the gut microbiome.[ref] (Read more about quercetin and how it is absorbed and metabolized.)

Curcumin: A placebo-controlled clinical trial found that NAFLD patients who took 1500 mg curcumin/day saw a significant decrease in liver fibrosis and inflammation.[ref]

NAC: N-acetyl cysteine supplementation decreased liver enzymes after three months.[ref]

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