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PNPLA3, CGI-58, and Inhibition of Hepatic Triglyceride Hydrolysis in Mice

Yang Wang1, Nora Kory1, Soumik BasuRay1

  • 1Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, TX.

Hepatology (Baltimore, Md.)
|February 26, 2019
PubMed

Insights

The PNPLA3 148M variant promotes fatty liver by inhibiting triglyceride hydrolysis. This occurs through a mechanism dependent on its interaction with CGI-58, affecting ATGL activity on lipid droplets.

Area of Science:

  • Biochemistry
  • Cell Biology
  • Genetics

Background:

  • A common variant in patatin-like phospholipase domain-containing protein 3 (PNPLA3 148M) is a significant risk factor for fatty liver disease.
  • The precise pathogenic mechanism linking PNPLA3 148M to liver disease progression remains unclear.
  • Previous research indicated PNPLA3 148M accumulates on hepatic lipid droplets (LDs).

Purpose of the Study:

  • To investigate the impact of PNPLA3 148M accumulation on hepatic triglyceride (TG) hydrolysis.
  • To elucidate the molecular mechanism by which PNPLA3 influences TG metabolism and fatty liver disease.
  • To determine the role of PNPLA3 interaction with ATGL and its cofactor CGI-58 in TG hydrolysis.

Main Methods:

  • Overexpression of PNPLA3 (wild type and 148M variant) and adipose triglyceride lipase (ATGL) in cultured hepatoma cells.
  • Analysis of lipid droplet (LD) content and ATGL localization upon co-expression.
  • Experiments in liver-specific Cgi-58 knockout (KO) mice to assess PNPLA3 function in vivo.
  • Co-immunoprecipitation and pulldown assays to investigate direct protein interactions.

Main Results:

  • PNPLA3 co-expression with ATGL inhibited LD depletion, indicating interference with TG hydrolysis.
  • PNPLA3 did not displace ATGL from LDs, suggesting an indirect inhibitory mechanism.
  • PNPLA3 and CGI-58 co-expression led to LD depletion, and PNPLA3 failed to localize to LDs in Cgi-58 KO mice.
  • PNPLA3 148M overexpression increased hepatic TG levels in wild-type but not in Cgi-58 KO mice.
  • Direct interaction between PNPLA3 and CGI-58 was confirmed through biochemical assays.

Conclusions:

  • PNPLA3 148M promotes hepatic steatosis by inhibiting ATGL-mediated TG hydrolysis.
  • This inhibition is dependent on the presence of CGI-58, suggesting PNPLA3 interferes with ATGL activity via its cofactor.
  • PNPLA3 and CGI-58 directly interact, forming the basis for the observed inhibition of TG hydrolysis and promotion of fatty liver disease.

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