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

Hepatology. 2011 Aug;54(2):509-21. doi: 10.1002/hep.24402. Epub 2011 Jun 30.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Gene Expression Regulation
  • Glucose / metabolism*
  • Hepatocytes / metabolism
  • Homeostasis*
  • Lipid Metabolism / physiology*
  • Mice
  • Mice, Inbred C57BL
  • Phospholipases A2, Calcium-Independent / genetics
  • Phospholipases A2, Calcium-Independent / physiology*
  • Sterol Regulatory Element Binding Protein 1 / physiology

Substances

  • Srebf1 protein, mouse
  • Sterol Regulatory Element Binding Protein 1
  • PNPLA3 protein, mouse
  • Phospholipases A2, Calcium-Independent
  • Glucose