PNPLA3 mediates hepatocyte triacylglycerol remodeling

Abstract

a single-nucleotide polymorphism (rs738409; C>G/I148M) in the patatin-like phospholipase domain containing 3 ( PNPLA3 , adiponutrin) gene, to be strongly associated with NAFLD. A meta-analysis of 16 studies demonstrated that homozygous carriers of PNPLA3 I148M have on the average a 73% higher liver fat content than weight-matched homozygous carriers of the major allele ( 5 ). However, NAFLD associated with PNPLA3I148M is distinct from obesity-associated common NAFLD, as it is not characterized by features of the metabolic syndrome such as hyperinsulinemia or dyslipidemia ( 1, 5 ).In vitro assays using recombinant PNPLA3 have suggested that the WT PNPLA3 (PNPLA3 WT ) hydrolyzes emulsifi ed triacylglycerol (TAG) and that the I148M substitution in PNPLA3 (PNPLA3 I148M ) abolishes this activity ( 6-8 ). Moreover, the protein was shown to display a transacylase activity ( 7 ), and to prefer oleic acid (18:1n-9) as the fatty acyl moiety ( 9 ). Opposing a putative role as a lipase, PNPLA3 is induced by glucose and insulin ( 10-12 ) and is a target gene of the lipogenic transcription factors SREBP-1c and the carbohydrate responsive element binding protein, ChREBP ( 13-16 ). Kumari et al. ( 17 ) suggested that the protein acts as lipogenic lysophosphatidic acid (LPA) acyltransferase, converting LPA to phosphatidic acid (PA), and that the I148M substitution increases this activity. Because PA acts as a precursor for both phospholipids and TAGs, this provided an alternative explanation for the hepatic fat accumulation in the PNPLA3 I148M

Treating liver fat and serum triglyceride levels in NAFLD, effects of PNPLA3 and TM6SF2 genotypes: Results from the WELCOME trial

“…The sample size calculation for the trial has been reported previously (26) and was based on change in liver fat % and not changes in serum TG concentration. The strengths of our study are the randomised double blind placebo- 20 controlled trial design that also included very detailed phenotyping of the patient cohort that enabled measurement of many potential confounders and a precise, quantitative measurement of % liver fat at baseline and at the end of study.…”

“…The PNPLA3 I148M GG genotype has been shown to reduce secretion of large TG-rich VLDL particles in obese men with hepatic steatosis and to impair apoB100 secretion (19). Moreover, the PNPLA3 I148M GG genotype is known to facilitate the differential incorporation into liver lipid droplets of different types of fatty acid, for example vaccenic and palmitoleic acids, thereby altering the fatty acid composition of the lipid droplets (20). Recent data suggest that in humans PNPLA3 I148M…”

“…These investigators also showed that there was a reduction of DHA in the hepatocytes of mice overexpressing PNPLA3 I148M GG genotype. Additionally, Ruhanen et al (20) have shown that fatty acid composition was altered in cells expressing PNPLA3 I148M GG genotype with an increase of 18:1 n-7 and 16:1 n-7 (vaccenic and palmitoleic acids, respectively).…”

“…regulates the efflux and remodelling, but not the influx, of lipid into hepatic lipid droplets (17,(20)(21)(22). In mice, Peter et al (23) have shown that PNPLA3I148M GG genotype is characterised by a decrease in lipolytic activity and lysophosphatidic acid acyl-CoA transferase activity, with a greater than twofold preference for PUFAs.…”

Angiopoietin-like 8 (Angptl8) controls adipocyte lipolysis and phospholipid composition

“…We failed to detect changes in the mRNA expression of central mediators of lipolysis, ATGL and HSL, while a small increase of the Angptl4 message was evident; Angptl4 acts as stimulator of adipocyte lipolysis (Gray et al, 2012), so its induction could contribute to the observed increase of lipolysis. In KD1 cells, which displayed a more potent enhancement of lipolysis than KD2, also a significant increase of the Pnpla3 mRNA was observed; Of note, Pnpla3 is known to enhance lipolysis and TG remodeling in hepatocytes (He et al, 2010;Ruhanen et al, 2014). Its elevated expression could thus facilitate the potent increase of lipolysis in KD1.…”