Regulation of Hepatic Triacylglycerol Metabolism by CGI-58 Does Not Require ATGL Co-activation

Caleb C. Lord, Daniel Ferguson, Gwynneth Thomas, Amanda L. Brown, Rebecca C. Schugar, Amy Burrows, Anthony D. Gromovsky, Jenna Betters, Chase Neumann, Jessica Sacks, Stephanie Marshall, Russell Watts, Martina Schweiger, Richard G. Lee, Rosanne M. Crooke, Mark J. Graham, Justin D. Lathia, Takuya F. Sakaguchi, Richard Lehner, Guenter HaemmerleRudolf Zechner, J. Mark Brown

Research output: Contribution to journalArticlepeer-review

36 Scopus citations

Abstract

Adipose triglyceride lipase (ATGL) and comparative gene identification 58 (CGI-58) are critical regulators of triacylglycerol (TAG) turnover. CGI-58 is thought to regulate TAG mobilization by stimulating the enzymatic activity of ATGL. However, it is not known whether this coactivation function of CGI-58 occurs in vivo. Moreover, the phenotype of human CGI-58 mutations suggests ATGL-independent functions. Through direct comparison of mice with single or double deficiency of CGI-58 and ATGL, we show here that CGI-58 knockdown causes hepatic steatosis in both the presence and absence of ATGL. CGI-58 also regulates hepatic diacylglycerol (DAG) and inflammation in an ATGL-independent manner. Interestingly, ATGL deficiency, but not CGI-58 deficiency, results in suppression of the hepatic and adipose de novo lipogenic program. Collectively, these findings show that CGI-58 regulates hepatic neutral lipid storage and inflammation in the genetic absence of ATGL, demonstrating that mechanisms driving TAG lipolysis in hepatocytes differ significantly from those in adipocytes.

Original languageEnglish
Pages (from-to)939-949
Number of pages11
JournalCell Reports
Volume16
Issue number4
DOIs
StatePublished - Jul 26 2016

Keywords

  • lipase
  • neutral lipid storage disease
  • triacylglycerol

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