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Mouse patatin‐like phospholipase domain‐containing 3 influences systemic lipid and glucose homeostasis

Human patatin‐like phospholipase domain‐containing 3 (PNPLA3) is associated with increased liver fat content and liver injury. Here, we show that nutritional status regulates 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 immunoprecipitation and electrophoretic mobility shift assays confirmed that SREBP‐1 proteins bound to the identified SREs. Furthermore, SREBP‐1c mediated the insulin and liver X receptor agonist TO901317‐dependent induction of PNPLA3 gene expression in hepatocytes. Adenovirus‐mediated overexpression of mouse PNPLA3 increased 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 the serum triglyceride level 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 directly targeted by SREBP‐1, promotes lipogenesis in primary hepatocytes and influences systemic lipid and glucose metabolism. (HEPATOLOGY 2011;)