A missense variant in human perilipin 2 ( Ser251Pro) reduces hepatic steatosis in mice.

Background & Aims: Non-alcoholic fatty liver disease (NAFLD) is characterised by the accumulation of lipid droplets (LDs) within hepatocytes. Perilipin 2 (PLIN2) is the most abundant protein in hepatic LDs and its expression correlates with intracellular lipid accumulation. A recently discovered coding variant, Ser251Pro (rs35568725), was found to promote the accumulation of small LDs in embryonic kidney cells. In this study, we investigate the role of -Ser251Pro (PLIN2-Pro251) on hepatic LD metabolism and research the metabolic phenotypes associated with this variant in humans.

Methods: For our animal model, we used knockout mice in which we expressed either human (Pro251 mice) or wild-type human (Ser251 mice) in a hepatocyte-specific manner. We fed both cohorts a lipogenic high-fat, high-cholesterol, high-fructose diet for 12 weeks.

Results: Pro251 mice were associated with reduced liver triglycerides (TGs) and had lower mRNA expression of fatty acid synthase and diacylglycerol O-acyltransferase-2 compared with Ser251 mice. Moreover, Pro251 mice had a reduction of polyunsaturated fatty acids-TGs and reduced expression of epoxygenase genes. For our human study, we analysed the Penn Medicine BioBank, the Million Veteran Program, and UK Biobank. Across these databases, the minor allele frequency of was approximately 5%. There was no association with the clinical diagnosis of NAFLD, however, there was a trend toward reduced liver fat in carriers by MRI-spectroscopy in UK Biobank subjects.

Conclusions: In mice lacking endogenous , expression of human attenuated high-fat, high-fructose, high-cholesterol, diet-induced hepatic steatosis compared with human wild-type . Moreover, Pro251 mice had lower polyunsaturated fatty acids-TGs and epoxygenase genes expression, suggesting less liver oxidative stress. In humans, is not associated with NAFLD.

Impact And Implications: Lipid droplet accumulation in hepatocytes is the distinctive characteristic of non-alcoholic fatty liver disease. Perilipin 2 (PLIN2) is the most abundant protein in hepatic lipid droplets; however, little is known on the role of a specific polymorphism on hepatic lipid droplet metabolism. attenuates liver triglycerides accumulation after a high-fat-high-glucose-diet. may be a novel lipid droplet protein target for the treatment of liver steatosis.