Mouse PNPLA3 Influences Systemic Lipid And Glucose Homeostasis

Nonalcoholic fatty liver disease (NAFLD) represents a spectrum of hepatic abnormalities associated with the accumulation of excess triglycerides in hepatocytes that varies in severity from steatosis to steatohepatitis, hepatic fibrosis and cirrhosis.Human patatin-like phospholipase domain-containing 3 (PNPLA3) is associated with increased liver fat content and liver injury. Here, we show that nutritional status regulated PNPLA3 gene expression in the mouse liver. Sterol response element binding protein-1 (SREBP-1) activated PNPLA3 gene transcription via sterol regulatory elements (SREs) mapped to the promoter region. Chromatin immunoprecipation and electrophoretic mobility shift assays confirmed that SREBP-1 proteins bound to the identified SREs. Furthermore, SREBP-1 c mediated the insulin and LXR agonist TO901317 dependent induction of PNPLA3 gene expression in hepatocytes. Adenovirus-mediated overexpression of mouse PNPLA3 increased the intracellular triglyceride content in primary hepatocytes, and knockdown of PNPLA3 suppressed the ability of SREBP-1c to stimulate lipid accumulation in hepatocytes. Finally, the overexpression of PNPLA3 in mouse liver increased serum triglyceride level, triglyceride content in the VLDL particles and hepatic VLDL secretion and impaired glucose tolerance; in contrast, the knockdown of PNPLA3 in db/db mouse liver improved glucose tolerance. Conclusion:Our data suggest that mouse PNPLA3, which is a lipogenic gene that is directly targeted by SREBP-1, promotes lipogenesis in primary hepatocytes and influences systemic lipid and glucose metabolism. FoxO transcription factors critically control fundamental cellular processes, including metabolism, cell differentiation and other reactions to cellular stress. SREBP-lc is as an important transcription factor in insulin-mediated lipogenesis signaling in hepatocytes. Recent studies have demonstrated that FoxO1 modulates the expression of SREBP-1c, but the exact mechanism remains unknown. Our results demonstrate that FoxO1 suppresses the SREBP-lc promoter transcriptional activity in HepG2 cells. This repression was independent of FoxO1 binding to the SREBP-1c promoter, but LXRE elements were crucial to this phenomenon. Moreover, FoxO1 also strongly inhibited the LXRa-mediated elevated transcription by SREBP-1c promoter. EMS A and ChIP further suggested the ability of FoxO1 to inhibit LXRαbinding with the LXRE. FoxO1-mediated suppression of SREBP-lc promoter activity could be partially alleviated by insulin.