The expression level of non-alcoholic fatty liver disease-related gene PNPLA3 in hepatocytes is highly influenced by hepatic lipid status.

Recent studies have suggested that variations in PNPLA3 are associated with non-alcoholic fatty liver disease (NAFLD). To gain insight into the potential function of PNPLA3 in liver, we have determined the effect of metabolic shifts on the hepatic expression profile of PNPLA3 in mice. PNPLA3 expression in wild-type C57BL/6 and NAFLD-susceptible LDL receptor knockout (LDLR-/-) mice was determined using microarray and real-time PCR analysis. PNPLA3 expression in livers is 50- to 100-fold lower as compared to (cardiac) muscle and adipose tissue in regular chow diet-fed mice. Feeding a Western-type diet stimulated hepatic relative PNPLA3 expression level 23-fold (p<0.001) both in C57BL/6 mice and LDLR-/- mice, suggesting that PNPLA3 does become an important player in hepatic lipid metabolism under conditions of lipid excess. Subjecting mice to fasting fully reversed the effect of the Western-type diet on hepatic PNPLA3 expression. Under these conditions, the expression level of PNPLA3 in adipose tissue is also decreased 90% (p<0.001). Cellular distribution analysis revealed that PNPLA3 is expressed in hepatocytes but not in liver endothelial and Kupffer cells. Microarray-based gene profiling showed that the expression level of PNPLA3 in hepatocytes is correlated with that of genes associated with the lipogenic pathway such as ME1, SPOT14, and SCD1. It appears that the NAFLD-related gene PNPLA3 is highly responsive to metabolic changes in hepatocytes within the liver and its relative change in expression level suggests an essential function in lipogenesis.