Nonalcoholic fatty liver disease (NAFLD) is a growing global health concern, characterized by the accumulation of extra fat in the liver. With no approved therapeutic medications currently available, lifestyle interventions, including dietary modifications, play a crucial role in managing NAFLD. The ketogenic diet, a high-fat, low-carbohydrate eating plan, has garnered attention as a potential therapeutic approach for NAFLD. This article explores the relationship between the keto diet and NAFLD, examining the potential benefits and risks, and providing a comprehensive overview of the current state of knowledge.
Understanding NAFLD
NAFLD, also known as simple steatosis, begins with the accumulation of triglycerides in the form of lipid droplets within hepatocytes. This occurs due to increased lipid acquisition through diet, de novo lipogenesis (DNL), and fatty acid mobilization from peripheral tissues.
A quarter of the global population is estimated to have NAFLD, and this figure may be even higher in the United States. Many people are unaware they have a fatty liver, as it often causes no pain or other symptoms, earning it the reputation of a "silent killer."
In some cases, NAFLD can progress to nonalcoholic steatohepatitis (NASH), where the liver becomes inflamed and damaged, potentially leading to scarring (fibrosis), cirrhosis, liver failure, and an increased risk of liver cancer.
Ketone Bodies: Fuel and Signaling Molecules
The ketone bodies, namely acetoacetate (AcAc), acetone, and β-hydroxybutyrate (βOHB), are small lipid-derived metabolites that act as an alternative form of energy for all forms of life. The levels of ketone bodies, AcAc and βOHB are abundant compared to acetone. Under physiological conditions, ketone bodies contribute 5-20% of total energy metabolism. Ketone body generation and utilization are influenced by various physiological cues, including nutrient deprivation, exercise, and calorie restriction, where their serum concentrations could rise from 100-250μM to 1 mM. Notably, ketone body levels also peak postnatal (10-15 days after birth) and reaches to 2-3 mM to support the huge energy demands of developing neonates. Short-term exposure to a fat-enriched diet, such as high-fat diet (HFD), also increases circulatory ketone bodies. Moreover, a ketogenic low-carb HFD increases serum ketone body levels above 2 mM. Elevated ketone bodies are also found in pathological conditions such as uncontrolled diabetes and alcoholic ketoacidosis, where the levels reach as high as 20 mM. However, the role of ketone bodies in pathological conditions remains to be elucidated.
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In addition to serving as fuel, ketone bodies act as a metabolic signal regulating diverse cellular functions. βOHB, but not acetone or AcAc, signals through the G-protein-coupled receptors (GPR), namely GPR109A, also known as the niacin receptor (HCAR2). GPR109A is highly expressed in adipose tissue and immune cells. GPR109A signaling in adipose tissue inhibits hormone-sensitive lipase-mediated lipolysis via repression of adenylyl cyclase. This has been proposed to play a critical role in inhibiting lipolysis in the adipose tissue, perhaps as a feedback mechanism to decrease ketone body synthesis by limiting the free fatty acid supply. βOHB signaling via GPR109A also regulates inflammation via NLRP3 (NOD-,LRR-and pyrin domain-containing protein 3), reverse cholesterol transport, atherosclerosis and neuroprotection. Ketone bodies also signal through the free fatty acid receptor (FFAR3), also known as GPR41, which was initially identified as a receptor for short-chain fatty acids (SCFAs). Under ketogenic conditions, activation of GPR41 in sympathetic ganglions suppresses energy expenditure. Thus, ketone bodies reduce lipolysis, sympathetic activity, and overall metabolic rate via GPRs.
βOHB is structurally similar to butyrate, which acts as an endogenous inhibitor of class I histone deacetylases (HDACs), the enzyme that deacetylates histone and non-histone proteins. Shimazu and colleagues demonstrated that βOHB inhibits class I HDACs in vitro with an IC50 of 2.4-5.3 mM, while AcAc inhibits class I HDACs at a higher concentration. Consistent with the role of ketone bodies in repressing HDACs, elevating ketone bodies via exogenous administration, fasting, or calorie deprivation increases the global histone acetylation marks on the chromatin. Thus, ketone bodies, via epigenetic mechanism, regulate the expression of several genes involved in anti-oxidant and anti-inflammatory response.
Hepatic Ketogenesis: The Production of Ketone Bodies
Ketogenesis occurs through a series of enzymatic reactions, wherein acetyl-CoA derived from the fatty acid β-oxidation is condensed to acetoacetyl-CoA via acetoacetyl-CoA thiolase in the mitochondrial matrix. Acetoacetyl-CoA is converted to hydroxymethyl glutaryl-CoA (HMG-CoA) by the mitochondrial rate-limiting ketogenic enzyme 3-hydroxy-3-methylglutaryl-CoA synthase 2 (HMGCS2, EC 2.3.3.10). HMG-CoA lyase (HMGCL, EC 4.1.3.4) then cleaves HMG-CoA to liberate acetyl-CoA and acetoacetate. β-OHB is generated from acetoacetate by the phosphatidylcholine-dependent mitochondrial enzyme D-βOHB dehydrogenase (BDH1, EC 1.1.1.30).
In mammals, ketogenesis primarily occurs in the liver due to the abundant expression of the HMGCS2 in the hepatocytes. Interestingly, hepatocytes do not express the ketolytic mitochondrial enzyme succinyl-CoA:3-oxo-acid CoA-transferase (SCOT, EC 2.8.3.5). Thus, hepatocytes only generate ketone bodies but cannot oxidize them. Ketone bodies are exported from the hepatocytes via the solute carrier family 16, member 6 (SLC16A6). Ketone body uptake in the target tissue occurs through monocarboxylate transporters (MCT1/2). The brain and heart are the primary users of ketone bodies, though a small amount is utilized by other organs. The ketone bodies are oxidized into acetyl-CoA. The acetyl-CoA enters into the TCA cycle or lipogenesis or is excreted in the urine.
The second highest expression of HMGCS2 is observed in the intestinal epithelial cells. A recent study showed that a loss of HMGCS2 in intestinal stem cells compromises their ability to differentiate and regenerate. Though, HMGCS2 expression is thought to be negligible in other mammalian cells; recent evidence shows that retinal pigment epithelium, kidney, heart, astrocytes, skeletal muscle, pancreatic β-cells, and beige adipocytes express HMGCS2 and produce ketone bodies in small amounts. Moreover, pathological conditions such as diabetes, kidney diseases and cardiovascular diseases induce HMGCS2 expression in extrahepatic tissues. But what remain unclear is the contribution of extrahepatic tissues to systemic ketone body levels. A recent study using liver specific-HMGCS2 knock-out mice demonstrated that the circulatory ketone bodies are derived from the liver. Thus, the extrahepatic tissues are speculated to have no contribution to the circulating pool of ketone bodies under steady state. Whether the ketone bodies exert local effect in the target tissue remains unclear.
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Regulation of Hepatic Ketogenesis
Hepatic ketogenesis is regulated by nutritional and physiological cues. For instance, the postnatal increase in hepatic ketogenesis is attributed to a surplus of dietary fat from breast milk. Thus, early weaning of mice reduces serum ketone levels due to a decrease in dietary fat. Similarly, HFD-mediated increase in serum fatty acids induces hepatic ketogenesis and elevates serum ketone body levels. These data partially denote that dietary fatty acids act as primary substrates for hepatic ketogenesis. Not surprisingly, mobilization of free fatty acids from the adipose tissue is directly proportional to hepatic ketogenesis. There exists a concept of a precursor-product relationship between total fat oxidation and hepatic ketogenesis. Adipose tissue lipolysis elevates serum free fatty acids. Studies show that inhibiting adipose tissue lipolysis by disrupting adipose triglyceride lipase (ATGL) abrogates increasing serum ketone bodies suggesting that adipose tissue-derived fatty acids are necessary for hepatic ketogenesis. However, it remains unclear whether ATGL inhibition impact hepatic ketogenesis in diet-induced obesity, where circulating fatty acids are elevated. Conflicting data also show that free fatty acids can be elevated in vivo without an increase in the ketone bodies. Inversely, ketosis could be reversed in situations of elevated serum free fatty acids. Therefore, these in vivo studies indicate that the rate of hepatic ketogenesis is not dependent solely upon the substrate availability i.e., fatty acids. Moreover, it is also possible that the continuous accumulation of fatty acids in the liver could potentially induce oxidative, mitochondrial stress, and even insulin resistance, which can impact ketogenesis. Seemingly, the hormonal, transcriptional, and post-translational modifications in the liver coordinate the maximal rate of ketone body synthesis.
Various physiological cues regulate hepatic ketogenesis through diverse mechanisms at hormonal, transcriptional, and post-translational levels. For example, the expression and activity of HMGCS2 is regulated by insulin and glucagon. Insulin inhibits hepatic ketogenesis by suppressing HMGCS2 expression in the liver and limiting substrate availability via reducing adipose tissue lipolysis. Conversely, glucagon promotes HMGCS2 expression via the transcription factor peroxisome proliferator-activated receptor alpha (PPARα) and increases the ketogenic flux of fatty acids. Other hormones, such as epinephrine and norepinephrine, also activate ketogenesis by stimulating lipolysis. At the transcriptional level, PPARα family of transcription factors regulate Hmgcs2 expression in various tissues. In the liver, PPARα is the primary regulator of Hmgcs2 and ketogenesis. Thus, mechanisms that regulate PPARα transcriptional activity in the liver modulates hepatic ketogenesis. For instance, PPARα transcriptional activity is inhibited by the mammalian target of rapamycin complex 1 (mTORC1), resulting in the suppression of Hmgcs2 expression and ketogenesis. In intestine stem cells and colonocytes, PPARα and PPARγ regulate Hmgcs2 expression, respectively. Other transcription factors, such as forkhead box 2 (FOXA2) are also shown to regulate Hmgcs2 transcription. Similarly, the circadian expression of HMGCS2 is regulated by the liver period 2 (PER2) via an unknown mechanism. In addition to positive regulators, several transcription factors act as negative regulators of ketogenesis. For example, hepatocyte nuclear factor 4 (HNF4) represses Hmgcs2 expression.
The post-translational modifications such as succinylation, acetylation, and palmitoylation regulate HMGCS2 enzyme activity. Shimazu et.al demonstrated that acyltransferases acetylate HMGCS2 at Lys 310, 447 and 473. Using genetic in vivo models, the authors showed that deacetylation of HMGCS2 by sirtuin 3 (SIRT3), which belongs to the deacetylase/ADP-ribosylase family of sirtuins, increases HMGCS2 enzyme activity. SIRT3 also activates the enzymes involved in fatty acid oxidation, such as LCAD, contributing to the induction of hepatic ketogenesis. Succinylation also represses HMGCS2 activity by binding to and competitively inhibiting the active site. For example, Quant et.al showed that the attachment of succinyl-CoA to the catalytic cysteine residue on HMGCS2 blocks the binding of acetoacetyl-CoA to the substrate. Glucagon enhances HMGCS2 enzyme activity by decreasing the levels of succinyl-CoA. It is interesting to note that the enzymes involved in the generation of ketone bodies are heavily succinylated. In particular, Hmgcs2 is succinylated at least on 15 lysine residues. Conversely, the post-translational modification via palmitoylation has been shown to increase HMGCS2 enzyme activity. Thus, the enzymatic activity of HMGCS2 is regulated through post-translational modifications under both physiological and pathological conditions.
The Ketogenic Diet: A Potential Therapeutic Approach for NAFLD
The ketogenic diet is a high-fat, moderate-protein, and very low-carbohydrate diet. The total daily distribution of macronutrients is typically 5-10% carbohydrates (and no more than 50 g), 60 to 80-90% fat (depending on the individuals therapeutic need), and 10-30% protein. These ranges allow a degree of flexibility for individual cases, and when used for different purposes. For example, treatment of intractable epilepsy usually requires a much higher proportion of fat while keeping carbohydrate consumption extremely low. The maximum amount of protein that can safely be consumed without compromising the efficacy of the diet remains somewhat unclear. In contrast, standard dietary approaches typically suggest obtaining up to 35% of energy from fat (including up to 10% from saturated fats), 45-75% from carbohydrates (up to 10% from sugars), and 10-35% from protein. In addition to the percentage of macronutrients, important (and often neglected) is the quality of formulation of the diet. For example, diet soda and pepperoni sausage would constitute a ketogenic diet, but no one could claim this would be healthy. Depending on the purpose of a KD, the proportion of macrocomponents can be modified by increasing the percentage of protein in the diet while decreasing the percentage of fat (e.g., the modified Atkins diet).
As compensation for the large influx of lipids, mitochondrial β-oxidation, a critical oxidative pathway for the disposal of NEFAs is upregulated. This results in the accumulation of acetyl-CoA, which has two fates; either undergo oxidation through the tricarboxylic acid (TCA) cycle or condense in the ketogenic pathway to form ketone bodies. Ketogenesis disposes of as much as three-fold fat entering the liver.
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Potential Benefits of Keto Diet in NAFLD
Several mechanisms suggest that the ketogenic diet may have a beneficial effect on NAFLD:
- Weight Loss: The ketogenic diet can promote weight loss, which is a primary goal in NAFLD management. Successful weight reduction is associated with a reduction in liver enzyme levels and an improvement in histological findings related to liver steatosis, inflammation, and fibrosis.
- Reduced Insulin Resistance: Insulin resistance is a key factor in NAFLD development. The ketogenic diet has been shown to improve insulin sensitivity by reducing blood glucose and insulin concentrations. This is achieved through several mechanisms, including body weight reduction, the absence of monosaccharides in the diet, and the elimination of fructose.
- Decreased De Novo Lipogenesis (DNL): The ketogenic diet restricts carbohydrate intake, which can reduce DNL, the process by which the liver converts excess carbohydrates into fat.
- Anti-inflammatory Effects: Ketone bodies, particularly β-hydroxybutyrate (BHB), have demonstrated anti-inflammatory properties. BHB can reduce NLRP3 inflammasome-mediated interleukin (IL)-1β and IL18 production, key inflammatory cytokines related to obesity and insulin resistance.
- Improved Satiety: Ketone bodies generated in response to carbohydrate restriction could further facilitate weight loss by promoting satiety, leading to a reduction in total energy intake.
Scientific Evidence: Studies on Keto Diet and NAFLD
Several studies have investigated the effects of ketogenic diets on NAFLD. Some short-term human studies have shown promising results, including rapid reductions in liver fat and improved insulin resistance.
- A 2020 study showed that a 6-day controlled ketogenic diet in adults with nonalcoholic fatty liver disease showed rapid reductions in liver fat and better insulin resistance.
- A 2025 review of very-low-calorie keto diets (VLCKD) showed substantial reductions in liver fat, improved insulin sensitivity, and lower liver enzyme levels.
However, it is important to note that long-term safety data, especially in individuals with advanced liver disease like cirrhosis, are still limited.
- A study by Tendler et al. placed five patients with biopsy-proven NAFLD on a restricted diet of <20 g/day of carbohydrates for 6 months without total calorie restriction. At the end of the study period, the patients had an average weight reduction of 10.9%. On follow-up liver biopsy, a significant reduction in the degree of hepatic steatosis was observed, with a trend towards improvement in liver fibrosis.
- Mardinoglu et al. conducted a single arm interventional study in which 10 Nordic patients with NAFLD were instructed to consume <30 g/day of carbohydrates, without total energy restriction. The average energy intake was 3,115 kcal/day). They observed a significant reduction in hepatic fat content of 43.8% despite a minimal weight loss of 1.8%.
- Wolver et al. demonstrated interesting outcomes of VLCKD for 6-months. with significant improvement of both liver steatosis and liver fibrosis.
- Kirk et al., observed a similar degree of weight loss in patients in VLCKD and low-calorie control diet. The intrahepatic triglyceride content decreased significantly from baseline but was not different in the two groups at the end of the study.
- Holmer et al. conducted an RCT in patients with NAFLD who received a standard of care (SoC) or VLCKD for 12 weeks. Patients in the VLCKD arm experienced a significantly greater weight loss and intrahepatic fat content reduction, despite a smaller reduction in daily total energy intake.
- Gepner et al. conducted a study in 278 patients, with 139 on a VLCKD with 40 g/day of carbohydrates for 2 months and was gradually increased to 70 g/day for a total of 18 months with a Mediterranean-style diet (Med/LC). The control group included 139 patients on a low-fat diet for the 18 month period. The reduction in liver fat content was significantly greater in the Med/LC group than in the low-fat diet group.
Potential Risks and Considerations
While the ketogenic diet may offer benefits for NAFLD, it is essential to be aware of the potential risks and considerations:
- Nutrient Deficiencies: Ketogenic diets require an extreme avoidance of carbohydrate foods. Carbohydrates are a good source of vitamins, minerals, and bioactive compounds such as polyphenols, and thus long-term exposure to a ketogenic diet can result in micronutrient inadequacy or deficiency if the diet is not appropriately guided.
- Adverse Effects: Some studies have reported adverse effects following VLCKD, such as muscle cramping, dyspepsia, nausea, headache, or vertigo. In addition, a case series reported that two cirrhotic patients tolerated VLCKD well for weight reduction for 28-30 weeks before liver transplantation without significant adverse effects. Nonetheless, elevation of total bilirubin was observed at the end of the VLCKD period in both patients, and elevations in serum alanine transaminase (ALT) and creatinine were observed in one patient.
- Impact on Advanced Liver Disease: Several animal studies suggest that the keto diet may worsen liver injury in the context of fibrosis or cirrhosis. A 2021 study in mice found that a high fat ketogenic diet increased cholesterol buildup in the liver and increased liver inflammation and markers of scarring.
- Sustainability: Fad diets can be difficult to stick with, especially if they cut out tasty items entirely. Rapid weight loss is not recommended because it’s rarely sustainable.
Alternative Dietary Approaches: Intermittent Fasting
In addition to the ketogenic diet, intermittent fasting (IF) has emerged as another dietary pattern of interest in NAFLD management. IF refers to a period of voluntary abstinence from food and/or drink for caloric restriction, or no caloric intake over a specified period of time. There are three types of IF: alternate-day fasting (ADF), periodic fasting, and time-restricted fasting (TRF). Generally, people following IF have approximately 10% or 300 kcal less energy intake than people taking normal diets or in non-fasting periods.
Scientific Evidence: Studies on Intermittent Fasting and NAFLD
Several studies have evaluated the effects of IF on NAFLD patients.
- A study included 83 patients in Iran and demonstrated that those who fasted during Ramadan had greater weight loss and improvement in hepatic steatosis grade on ultrasound than those who did not fast. Improvements in liver enzymes and cholesterol levels were also observed in the RF group.
- Cai et al. randomly assigned patients to an ADF with a 25% caloric intake on fasting days or a control group for 12 weeks. Patients in ADF group had a lower daily energy intake, end-of-study weight, and total body fat mass. Nevertheless, the degree of liver fibrosis measured by transient elastography, was not improved and was comparable to that in the control group.
- Johari et al., reported greater weight loss, greater reduction in hepatic steatosis grade, and improved liver fibrosis measured by shear wave elastography in patients with modified ADF with 70% caloric intake during fasting days, compared with patients who consumed their usual diet for a duration of 8 weeks.
- Cai et al. compared the outcomes of TRF using the 8:16 h method with SoC outcomes. Intriguingly, the TRF group had a greater weight loss than the SoC group even though the daily caloric intake appeared to be a little higher in the TRF group. The study showed no change in the extent of liver fibrosis, but the patients had a high degree of fibrosis, with a mean liver stiffness >18 kPa, which is comparable to stage 4 fibrosis or cirrhosis, in both groups.
- Hodge et al. conducted an RCT using TRF as IF. Patients in IF arm had a significant reduction in both liver steatosis and liver fibrosis measured by liver stiffness. The same results were not observed in patients in the control group despite similar degrees of body mass index (BMI) reduction.
- Holmer et al. evaluated and compared the effects of IF and SoC on patient outcome. The IF group used the 5:2 dietary approach with a caloric restriction of 500 cal/day in women and 600 kcal/day in men for two non-consecutive days per week. Patients in the IF group had a greater reduction in daily caloric intake, lost more weight, and had a greater reduction in hepatic steatosis than those in the SoC group. Moreover, an improvement in hepatic fibrosis measured by transient elastography was observed in both groups.
Potential Risks and Considerations of Intermittent Fasting
IF is simple and relatively safe for most people, with fewer safety concerns compared with a ketogenic diet. Possible concerns related to IF include hypoglycemia in patients with diabetes receiving insulin therapy or insulinogenic drugs and hypotension in patients taking antihypertensive medications. In addition, in patients with liver cirrhosis undergoing IF, overnight fasting can mimic 72 h starvation, resulting in malnutrition and increased complications. IF can also aggravate starvation effects, thereby causing negative outcomes. There is also a concern that IF could trigger binge eating, i.e. overeating after food is made available, as IF requires a shift in regular mealtimes.
General Recommendations for Managing NAFLD
Beyond specific dietary approaches, several general recommendations can help manage NAFLD:
- Balanced Diet: Eat a well-balanced diet that features high-fiber foods, vegetables, fruits, fish, lean meats, nuts, eggs, seeds, and unrefined oils.
- Limit Unhealthy Fats and Sugars: Don’t overdo it on fats, especially from processed foods. Fructose and other sugars are a major concern as well, especially in sodas, candy, sugary cereals, sweetened juices, and fast food.
- Moderate Exercise: Consider moderate exercise to avoid a condition called sarcopenia, or low muscle mass and strength.
- Limit Alcohol Consumption: Even moderate alcohol consumption can cause issues.