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PNPLA3-A Potential Therapeutic Target for Personalized Treatment of Chronic Liver Disease

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PNPLA3-A Potential Therapeutic Target for Personalized Treatment of Chronic Liver Disease

Xiaocheng Charlie Dong. Front Med (Lausanne).

Abstract

Patatin-like phospholipase domain-containing protein 3 (PNPLA3) is a lipid droplet-associated protein that has been shown to have hydrolase activity toward triglycerides and retinyl esters. The first evidence of PNPLA3 being associated with fatty liver disease was revealed by a genome-wide association study (GWAS) of Hispanic, African American, and European American individuals in the Dallas Heart Study back in 2008. Since then, numerous GWAS reports have shown that PNPLA3 rs738409[G] (148M) variant is associated with hepatic triglyceride accumulation (steatosis), inflammation, fibrosis, cirrhosis, and even hepatocellular carcinoma regardless of etiologies including alcohol- or obesity-related and others. The frequency of PNPLA3(148M) variant ranges from 17% in African Americans, 23% in European Americans, to 49% in Hispanics in the Dallas Heart Study. Due to high prevalence of obesity and alcohol consumption in modern societies, the PNPLA3(148M) gene variant and environment interaction poses a serious concern for public health, especially chronic liver diseases including alcohol-related liver disease (ALD) and nonalcoholic fatty liver disease (NAFLD). Therefore, PNPLA3(148M) variant is a potential therapeutic target for chronic liver disease in the rs738409 allele carriers. Currently, there is no approved drug specifically targeting the PNPLA3(148M) variant yet. With additional mechanistic studies, novel therapeutic strategies are expected to be developed for the treatment of the PNPLA3(148M) variant-associated chronic liver diseases in the near future.

Keywords: PNPLA3; alcoholic liver disease; cirrhosis; fibrosis; hepatocellular carcinoma; nonalcoholic steatohepatitis; rs738409.

Figures

Figure 1
Figure 1
PNPLA family members. Nine PNPLA family members are depicted by the size and localization of the conserved patatin (PAT) domains.
Figure 2
Figure 2
Human and mouse Pnpla3 protein sequence alignments. The protein sequences were aligned using the NCBI BLAST program. The identical residues are in red. The PAT domain is underlined. The 148I residue is marked by asterisk.
Figure 3
Figure 3
A working model for the PNPLA3 function on lipid droplet. ATGL and ABHD5 normally interact to promote triglyceride breakdown from lipid droplets. The 148M mutation impairs the turnover of PNPLA3 protein by ubiquitin or autophagy mediated degradation. When PNPLA3(148M) variant proteins accumulate on lipid droplets, PNPLA3(148M) competes with ATGL for the interaction with ABHD5. As a result, the ATGL activity is reduced and lipid droplets are accumulated.
Figure 4
Figure 4
PNPLA3(148M) is associated with a wide-spectrum of chronic liver diseases. Hepatic accumulation of PNPLA3(148M) protein leads to triglyceride accumulation, liver injury, and fibrosis. With different etiologies, this may lead to the development of various liver disorders including NAFLD, NASH, ALD, alcoholic hepatitis (AH), cirrhosis, and HCC.

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