Circulating Triacylglycerol Signatures in Nonalcoholic Fatty Liver Disease Associated With the I148M Variant in PNPLA3 and With Obesity

Abstract

We examined whether relative concentrations of circulating triacylglycerols (TAGs) between carriers compared with noncarriers of PNPLA3 I148M gene variant display deficiency of TAGs, which accumulate in the liver because of defective lipase activity. We also analyzed the effects of obesity-associated nonalcoholic fatty liver disease (NAFLD) independent of genotype, and of NAFLD due to either PNPLA3 I148M gene variant or obesity on circulating TAGs. A total of 372 subjects were divided into groups based on PNPLA3 genotype or obesity. Absolute and relative deficiency of distinct circulating TAGs was observed in the PNPLA3 148MM/148MI compared with the PNPLA3 148II group. Obese and 'nonobese' groups had similar PNPLA3 genotypes, but the obese subjects were insulinresistant. Liver fat was similarly increased in obese and PNPLA3 148MM/148MI groups. Relative concentrations of TAGs in the obese subjects versus nonobese displayed multiple changes. These closely resembled those between obese subjects with NAFLD but without PNPLA3 I148M versus those with the I148M variant and NAFLD. The etiology of NAFLD influences circulating TAG profiles. 'PNPLA3 NAFLD' is associated with a relative deficiency of TAGs, supporting the idea that the I148M variant impedes intrahepatocellular lipolysis rather than stimulates TAG synthesis. 'Obese NAFLD' is associated with multiple changes in TAGs, which can be attributed to obesity/insulin resistance rather than increased liver fat content per se.

Compounds of the sphingomyelin-ceramide-glycosphingolipid pathways as secondary messenger molecules: new targets for novel therapies for fatty liver disease and insulin resistance

“…Adiponectin increases Cer catabolism, resulting to increased formation of an antiapoptotic metabolite, sphingosine-1-phosphate (S1P). This catabolic process is independent of AMP-dependent kinase (AMPK) (30,74,78). Overproduction of adiponectin decreases caspase-8-mediated death, whereas genetic ablation of adiponectin enhances apoptosis in vivo through a sphingolipid-mediated pathway.…”

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

“…In NAFLD, patients with the homozygous GG (I148M) gene variant of the patatin-like phospholipase domain-containing protein-3 (PNPLA3) have higher levels of liver fat accumulation (15,16) and lower serum fasting TG concentration, compared to those without the homozygous gene variant (17). The precise mechanism by which variation in PNPLA3 genotype induces hepatic lipid accumulation and decreased fasting triglyceride concentration is not clear.…”

“…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.…”

Circulating phospholipid profiling identifies portal contribution to NASH signature in obesity

“…Recently, variation in circulatory TAG profiles served as a basis to define phenotypic heterogeneity in NASH i.e. PNPLA3 or obesity-associated NASH [27].…”