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.

Figure 1

Hypothetical mechanism of hepatic fat accumulation associated with the 148 Isoleucine to Methionine protein variant patatin-like phospholipase domain-containing 3 polymorphism. ER: Endoplasmic reticulum; LPA: Lyso-phosphatidic acid; PA: Phosphatidic acid; Tg: Triglycerides; ?: To be confirmed; PNPLA3: Patatin-like phospholipase domain-containing 3.

Figure 2

Hypothetical mechanisms linking the 148 Isoleucine to Methionine protein variant of patatin-like phospholipase domain-containing 3 polymorphism with hepatic fibrogenesis in the presence of triggering factors for steatosis (Obesity and insulin resistance, excessive alcohol intake and chronic hepatitis C virus infection). A: Direct effect of mutant 148 Isoleucine to Methionine protein variant patatin-like phospholipase domain-containing 3 (148M PNPLA3) on inflammation, oxidative stress, and cellular damage (ballooning) in hepatocytes with secondary activation of non-parenchymal cells, including Kupffer cells (KC) and hepatic stellate cells (HSC). Hepatocytes are shown in brown, KC in light green, neutrophils in dark green, HSC in blue. Nuclei are shown in darker shades of the cell color, whereas lipid droplets and steatosis in yellow, and ballooning (endoplasmic reticulum swelling) in white; B: Direct effect of the mutant 148M PNPLA3 on the activation of non-parenchymal cells. Mutant PNPLA3 (148Met) is shown as a red box.