Regulator of G protein signaling (Rgs16) inhibits hepatic fatty acid oxidation in a carbohydrate response element-binding protein (ChREBP)-dependent manner

Victor Pashkov, Jie Huang, Vinay K. Parameswara, Wojciech Kedzierski, Deborah M. Kurrasch, Gregory G. Tall, Victoria Esser, Robert D. Gerard, Kosaku Uyeda, Howard C. Towle, Thomas M. Wilkie

Research output: Contribution to journalArticle

29 Scopus citations

Abstract

Gprotein-coupled receptor (GPCR) pathways control glucose and fatty acid metabolism and the onset of obesity and diabetes. Regulators of G protein signaling (RGS) are GTPase-activating proteins (GAPs) for Gi and Gq α-subunits that control the intensity and duration of GPCR signaling. Herein we determined the role of Rgs16 in GPCR regulation of liver metabolism. Rgs16 is expressed during the last few hours of the daily fast in periportal hepatocytes, the oxygen-rich zone of the liver where lipolysis and gluconeogenesis predominate. Rgs16 knock-out mice had elevated expression of fatty acid oxidation genes in liver, higher rates of fatty acid oxidation in liver extracts, and higher plasma β-ketone levels compared with wild type mice. By contrast, transgenic mice that overexpressed RGS16 protein specifically in liver exhibited reciprocal phenotypes as well as low blood glucose levels compared with wild type littermates and fatty liver after overnight fasting. The transcription factor carbohydrate response element-binding protein (ChREBP), which induces fatty acid synthesis genes in response to high carbohydrate feeding, was unexpectedly required during fasting for maximal Rgs16 transcription in liver and in cultured primary hepatocytes during gluconeogenesis. Thus, RGS16 provides a signaling mechanism for glucose production to inhibit GPCR-stimulated fatty acid oxidation in hepatocytes.

Original languageEnglish (US)
Pages (from-to)15116-15125
Number of pages10
JournalJournal of Biological Chemistry
Volume286
Issue number17
DOIs
StatePublished - Apr 29 2011

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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    Pashkov, V., Huang, J., Parameswara, V. K., Kedzierski, W., Kurrasch, D. M., Tall, G. G., Esser, V., Gerard, R. D., Uyeda, K., Towle, H. C., & Wilkie, T. M. (2011). Regulator of G protein signaling (Rgs16) inhibits hepatic fatty acid oxidation in a carbohydrate response element-binding protein (ChREBP)-dependent manner. Journal of Biological Chemistry, 286(17), 15116-15125. https://doi.org/10.1074/jbc.M110.216234