Genetic Factors in the Pathogenesis of Nonalcoholic Fatty Liver and Steatohepatitis

Paola Dongiovanni, Stefano Romeo, Luca Valenti, Paola Dongiovanni, Stefano Romeo, Luca Valenti

Abstract

Liver fat accumulation generally related to systemic insulin resistance characterizes nonalcoholic fatty liver disease (NAFLD), which in the presence of nonalcoholic steatohepatitis (NASH) can progress towards cirrhosis and hepatocellular carcinoma. Due to the epidemic of obesity, NAFLD is now the most frequent liver disease in Western countries. Epidemiological, familial, and twin studies provide evidence for a strong genetic component of NAFLD susceptibility. Recently, genome-wide association studies led to the identification of the major inherited determinants of hepatic fat accumulation: patatin-like phospholipase domain-containing 3 (PNPLA3) I148M gene and transmembrane 6 superfamily member 2 (TM6SF2) E167K gene variants, involved in lipid droplets remodelling and very low-density lipoproteins secretion, are the major determinants of interindividual differences in liver steatosis, and susceptibility to progressive NASH. In this review, we aimed to provide an overview of recent insights into the genetics of hepatic fat accumulation and steatohepatitis.

Figures

Figure 1
Figure 1
Molecular genetics of NASH. (a) NAFLD is characterized by the hepatic fat accumulation in lipid droplets resulting from an unbalance between triglycerides acquisition and secretion. FFA stored as triglycerides during hepatic steatosis derive from peripheral lipolysis related to adipose tissue insulin resistance, followed by de novo lipogenesis induced by hyperinsulinemia, and excessive food intake. In the liver, FFA can be catabolized through β-oxidation and reesterification to triglycerides and stored as lipid droplets or exported as VLDL. (b) PNPLA3 I148M variant is attached on the surface of lipid droplets reducing triglyceride breakdown leading to lipid retention in the hepatocyte lipid droplet. (c) TM6SF2 E167K variant reduces triglycerides secretion through VLDL, leading to hepatocellular retention of lipids.

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