Genetic determinants of hepatic steatosis in man

Abstract

Hepatic steatosis is one of the most common liver disorders in the general population. The main cause of hepatic steatosis is nonalcoholic fatty liver disease (NAFLD), representing the hepatic component of the metabolic syndrome, which is characterized by type 2 diabetes, obesity, and dyslipidemia. Insulin resistance and excess adiposity are considered to play key roles in the pathogenesis of NAFLD. Although the risk factors for NAFLD are well established, the genetic basis of hepatic steatosis is largely unknown. Here we review recent progress on genomic variants and their association with hepatic steatosis and discuss the potential impact of these genetic studies on clinical practice. Identifying the genetic determinants of hepatic steatosis will lead to a better understanding of the pathogenesis and progression of NAFLD.

Fig. 1.

The histopathological progression of NAFLD. A: Normal liver (H&E, 200×). B: Macrovesicular steatosis (H&E, 100×). C: Neutrophils surrounding Mallory bodies (H&E, 400×). D: Cirrhotic nodule with steatosis (MT, 100×). H&E, hematoxylin and eosin; MT, Masson's trichrome; NAFLD, nonalcoholic fatty liver disease.

Fig. 2.

Overview of the metabolic processes influencing the development of NAFLD. Variants within genes involved in these processes may impact the development and/or progression of NAFLD. NAFLD, nonalcoholic fatty liver disease.

Fig. 3.

Median hepatic fat content and PNPLA3 I148M genotypes in European-Americans, African-Americans, and Hispanics in the Dallas Heart Study. PNPLA3, patatin-like phospholipase domain containing 3, adiponutrin. Reprinted by permission from Macmillan Publishers Ltd: Nat Genet 2008;40:1461-5, copyright 2008.

Fig. 4.

Structural model of wild-type and I148M PNPLA3. The domain structure of PNPLA3, showing the patatin-like domain (black) and locations of the catalytic dyad (Ser47 and Asp166) and the I148M substitution. Structure models of normal (Ile148) and mutant (Met148) PNPLA3 are shown in the left and right panels, respectively. Protein traces are rainbow-colored from N to C terminus (blue to red) with side chains of catalytic dyad residues (positions 47 and 166). The dots indicate a space-filling model corresponding to van der Waals atomic radii. Oxygen and sulfur atoms are colored red and yellow, respectively. PNPLA3, patatin-like phospholipase domain containing 3, adiponutrin. Reprinted by permission from He et al. J Biol Chem 2010;285:6706-15.