A single nucleotide polymorphism of PLIN2 is associated with nonalcoholic steatohepatitis and causes phenotypic changes in hepatocyte lipid droplets

Perilipin 2 (PLIN2) is a lipid droplet-associated protein which regulates cellular lipid storage and is highly expressed in the liver. Previous studies of a missense single nucleotide polymorphism (SNP) in PLIN2, Ser251Pro, (i.e. rs3556875) have shown this SNP to cause decreased lipolysis and increased intracellular lipid accumulation. To explore if this SNP is associated with nonalcoholic steatohepatitis (NASH), we genotyped a discovery cohort of 116 adults with NASH and 67 age- and gender-matched controls. rs3556875 was significantly associated with NASH with an allelic odds ratio of 2.98 (95% confidence interval 1.12-7.31, p=0.02) as well as in a dominant inheritance model. In an in vitro model of hepatic steatosis, expression of the Pro251 variant protein led to phenotypic changes in intracellular lipid droplets, yielding smaller diameter and up to 7 fold more lipid droplets per cell when compared to wild type PLIN2. In conclusion, the Ser251Pro SNP of PLIN2 may convey risk for NASH and causes phenotypic changes in hepatocyte lipid droplets.