PNPLA3 I148M polymorphism and progressive liver disease

Abstract

The 148 Isoleucine to Methionine protein variant (I148M) of patatin-like phospholipase domain-containing 3 (PNPLA3), a protein is expressed in the liver and is involved in lipid metabolism, has recently been identified as a major determinant of liver fat content. Several studies confirmed that the I148M variant predisposes towards the full spectrum of liver damage associated with fatty liver: from simple steatosis to steatohepatitis and progressive fibrosis. Furthermore, the I148M variant represents a major determinant of progression of alcohol related steatohepatitis to cirrhosis, and to influence fibrogenesis and related clinical outcomes in chronic hepatitis C virus hepatitis, and possibly chronic hepatitis B virus hepatitis, hereditary hemochromatosis and primary sclerosing cholangitis. All in all, studies suggest that the I148M polymorphism may represent a general modifier of fibrogenesis in liver diseases. Remarkably, the effect of the I148M variant on fibrosis was independent of that on hepatic steatosis and inflammation, suggesting that it may affect both the quantity and quality of hepatic lipids and the biology of non-parenchymal liver cells besides hepatocytes, directly promoting fibrogenesis. Therefore, PNPLA3 is a key player in liver disease progression. Assessment of the I148M polymorphism will possibly inform clinical practice in the future, whereas the determination of the effect of the 148M variant will reveal mechanisms involved in hepatic fibrogenesis.

Keywords: Alcoholic liver disease; Chronic hepatitis C virus hepatitis; Fibrogenesis; Genetics; Hepatocellular carcinoma; Liver disease; Nonalcoholic fatty liver disease; Patatin-like phospholipase domain-containing 3; Single nucleotide polymorphism; Steatosis

Core tip: The 148 Isoleucine to Methionine protein variant (I148M) of patatin-like phospholipase domain-containing 3 (PNPLA3) has recently been identified as a major determinant of liver fat content. Several studies conducted in different ethnicities confirmed that I148M influences the full spectrum of liver damage: from simple steatosis to nonalcoholic steatohepatitis and progressive fibrosis to hepatocellular carcinoma. Furthermore, I148M turned out to represent a major determinant of progression of alcohol related steatohepatitis, and to influence fibrosis progression and related clinical outcomes in chronic hepatitis C virus hepatitis, as well as other in liver diseases. All in all, studies suggest that the PNPLA3 I148M polymorphism may represent a general modifier of fibrogenesis in liver diseases.