PNPLA3 I148M variant in nonalcoholic fatty liver disease: demographic and ethnic characteristics and the role of the variant in nonalcoholic fatty liver fibrosis

Abstract

Patatin-like phospholipase domain-containing 3 (PNPLA3 or adiponutrin) displays anabolic and catabolic activities in lipid metabolism, and has been reported to be significantly associated with liver fat content. Various studies have established a strong link between the 148 isoleucine to methionine protein variant (I148M) of PNPLA3 and liver diseases, including nonalcoholic fatty liver disease (NAFLD). However, detailed demographic and ethnic characteristics of the I148M variant and its role in the development of nonalcoholic fatty liver fibrosis have not been fully elucidated. The present review summarizes the current knowledge on the association between the PNPLA3 I148M variant and NAFLD, and especially its role in the development of nonalcoholic fatty liver fibrosis. First, we analyze the impact of demographic and ethnic characteristics of the PNPLA3 I148M variant and the presence of metabolic syndrome on the association between PNPLA3 I148M and NAFLD. Then, we explore the role of the PNPLA3 I148M in the development of nonalcoholic fatty liver fibrosis, and hypothesize the underlying mechanisms by speculating a pro-fibrogenic network. Finally, we briefly highlight future research that may elucidate the specific mechanisms of the PNPLA3 I148M variant in fibrogenesis, which, in turn, provides a theoretical foundation and valuable experimental data for the clinical management of nonalcoholic fatty liver fibrosis.

Keywords: Nonalcoholic fatty liver disease; Nonalcoholic fatty liver fibrosis; PNPLA3 I148M variant; Polymorphism.

Figure 1

Simplified schematic model showing the hypothetical molecular mechanism by which the PNPLA3 I148M variant participates in the development and progression of nonalcoholic fatty liver fibrosis. The hedgehog signaling pathway links PNPLA3 with the activation of hepatic stellate cells, which is considered as the central part of fibrogenesis. PNPLA3 protein exhibits activities of lysophosphatidic acid acyltransferase and acylglycerol hydrolase to maintain the TG balance in the liver. The “gain function” of the PNPLA3 I148M variant causes Triglyceride (TG) accumulation in the liver, which accelerates the progression of nonalcoholic fatty liver disease. HSC: Hepatic stellate cell.