The Genetic Variant I148M inPNPLA3Is Associated With Increased Hepatic Retinyl-Palmitate Storage in Humans

Abstract

The increased content of hepatic retinyl-palmitate and the reduced ratio of retinol/retinyl-palmitate in PNPLA3 I148M minor allele carriers support in vitro findings of an altered retinyl-palmitate lipase activity. Our results indicate that the PNPLA3 I148M variant is relevant for the retinyl-palmitate content in human liver, providing a possible link to chronic liver disease.

PNPLA3 gene in liver diseases

“…Consistently, obese and patients at risk for NASH with the PNPLA3 I148M allele have lower circulating concentrations of free retinol and retinol binding protein 4 [89]. Finally, a study examining differences in intrahepatic retinol from human liver samples showed higher concentrations of retinol in liver specimens from I148M mutation homozygotes [90]. Together, in vitro, human genetics, and ex vivo data suggest that carriers of the I148M mutation have intracellular retinol retention in hepatic stellate cells.…”

PNPLA3 and RNF7 Gene Variants are Associated with the Risk of Developing Liver Fibrosis and Cirrhosis in an Eastern European Population

“…Furthermore, the same group has recently shown that PNPLA3-mediated retinol release may protect against liver fibrosis [25]. Other studies have shown that the PNPLA3 I148M variant is relevant for the retinyl-palmitate content in human liver [26] and influences circulating retinol levels in adults [27]. A recent elegant study in mice has shown that PNPLA3 I148M knock-in mice accumulate PNPLA3 on lipid droplets and develop hepatic steatosis [28].…”

“…A later, large scale genome-wide associated study (GWAS) demonstrated J Gastrointestin Liver Dis, March 2017 Vol. 26 No 1: 37-43 that the patatin-like phospholipase domain containing 3 (PNPLA3) gene polymorphism rs738409 was associated with NAFLD [8] and affects the activities of liver enzymes in plasma [9]. The PNPLA3 gene polymorphism rs738409 was also shown to accelerate liver fibrosis progression rate in HCV-infected patients [10] and contribute to the development of alcoholic liver cirrhosis [11].…”

Nutrigenetics

“…Finally, a recent study has found an association between an SNP in PNPLA3 and blood RET concentration in patients with non-alcoholic fatty liver disease or obesity [105]. Of note, the same SNP has been associated in another study with increased RP liver storage [94].…”

“…Since methods to assess VA status remain expensive, the use of GWAS to identify genetic variations associated with VA status is a great challenge, and consequently, the information on the influence of genetic variations on VA status is scarce. Only one study has reported the association of an SNP with liver stores of VA: Kovarova et al [94] showed that an SNP in PNPLA3, a gene involved in the mobilization of retinyl esters stored in stellate cells [64], was associated with increased RP liver storage in a group of 42 patients undergoing liver surgery. Interestingly, the minor allele of the SNP is highly prevalent in populations from Latin American (about 70%), whereas it is found at a much lower frequency (around 20%) in populations from Europe and Africa [95].…”