Genetic Factors in Nonalcoholic Fatty Liver Disease

Nonalcoholic fatty liver disease (NAFLD) encompasses a spectrum from simple steatosis to nonalcoholic steatohepatitis (NASH), fibrosis and cirrhosis, arising in the absence of significant alcohol intake. Familial and population studies have demonstrated a strong heritable component, with genome-wide association studies (GWAS) pinpointing key variants in genes that regulate lipid storage, secretion and cellular stress. The I148M substitution in PNPLA3 alters triglyceride hydrolysis in hepatocytes and stellate cells, fostering lipid droplet accumulation and fibrogenic activation. A common E167K polymorphism in TM6SF2 reduces very low-density lipoprotein (VLDL) lipidation, promoting intracellular fat retention and accelerating fibrosis. The rs641738 variant near MBOAT7 influences phospholipid remodelling and has been linked to hepatocellular carcinoma risk in non-cirrhotic patients. Polygenic risk scores that integrate these and other loci correlate with disease severity, informing population stratification and guiding therapeutic targeting. Functional studies reveal that these variants converge on pathways of de novo lipogenesis, lipoprotein assembly and mitochondrial energetics, underscoring a global imperative to understand genetic susceptibility in diverse ethnic groups and to develop precision interventions.

Research from Nature Portfolio

Recent studies have defined the enzymatic role of wild-type PNPLA3 in vivo, demonstrating its preference for polyunsaturated triglycerides and its contribution to phospholipid desaturation and efficient VLDL secretion. Loss of this activity by the I148M variant exacerbates steatosis under lipogenic states and impairs lipid export. Investigations of TM6SF2 E167K have confirmed its causal link to hepatic fibrosis progression by revealing an independent association with advanced scarring, beyond established confounders. Further work on the MBOAT7 rs641738 C > T allele shows that reduced MBOAT7 expression in carriers predisposes to hepatocellular carcinoma in the absence of cirrhosis, suggesting that phospholipid remodelling influences oncogenic pathways and should be integrated into future risk stratification studies.

Genetic Factors in Nonalcoholic Fatty Liver Disease publication trend

The graph below shows the total number of articles in genetic factors in nonalcoholic fatty liver disease across all publications each year (not limited to Nature Index journals).

Technical terms

Single nucleotide polymorphism (SNP): A single base-pair variation in the genome that can affect gene function and disease risk.

De novo lipogenesis (DNL): The metabolic pathway by which acetyl-CoA is converted into fatty acids within the liver.

Very low-density lipoprotein (VLDL): A liver-derived particle that transports endogenous triglycerides and cholesterol through the bloodstream.

Ketogenesis: The process by which the liver converts fatty acids into ketone bodies, especially during fasting.

Fibrosis: The excessive accumulation of extracellular matrix proteins leading to scarring and organ dysfunction.

References

1. The PNPLA3 I148M variant increases ketogenesis and decreases hepatic de novo lipogenesis and mitochondrial function in humans. Cell Metabolism (2023).
2. PNPLA3 is a triglyceride lipase that mobilizes polyunsaturated fatty acids to facilitate hepatic secretion of large-sized very low-density lipoprotein. Nature Communications (2024).
3. TM6SF2 rs58542926 influences hepatic fibrosis progression in patients with non-alcoholic fatty liver disease. Nature Communications (2014).
4. PNPLA3 has retinyl-palmitate lipase activity in human hepatic stellate cells. Human Molecular Genetics (2014).
5. A Sequence Variation (I148M) in PNPLA3 Associated with Nonalcoholic Fatty Liver Disease Disrupts Triglyceride Hydrolysis*. Journal of Biological Chemistry (2009).
6. Inactivation of Tm6sf2, a Gene Defective in Fatty Liver Disease, Impairs Lipidation but Not Secretion of Very Low Density Lipoproteins*. Journal of Biological Chemistry (2016).
7. MBOAT7 rs641738 variant and hepatocellular carcinoma in non-cirrhotic individuals. Scientific Reports (2017).
8. Combined effects of the PNPLA3 rs738409, TM6SF2 rs58542926, and MBOAT7 rs641738 variants on NAFLD severity: a multicenter biopsy-based study 1. Journal of Lipid Research (2016).