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Regulator of G protein signaling (RGS16) inhibits hepatic fatty acid oxidation in a carbohydrate response element-binding protein (ChREBP)-dependent manner.

Abstract
G protein-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 G(i) and G(q) 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.
AuthorsVictor 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
JournalThe Journal of biological chemistry (J Biol Chem) Vol. 286 Issue 17 Pg. 15116-25 (Apr 29 2011) ISSN: 1083-351X [Electronic] United States
PMID21357625 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
Chemical References
  • Basic Helix-Loop-Helix Leucine Zipper Transcription Factors
  • Fatty Acids
  • Mlxipl protein, mouse
  • Nuclear Proteins
  • RGS Proteins
  • RGS16 protein
  • Receptors, G-Protein-Coupled
  • Transcription Factors
  • Glucose
Topics
  • Animals
  • Basic Helix-Loop-Helix Leucine Zipper Transcription Factors
  • Fatty Acids (biosynthesis, genetics, metabolism)
  • Gluconeogenesis
  • Glucose (biosynthesis, physiology)
  • Hepatocytes (metabolism)
  • Liver (metabolism)
  • Mice
  • Mice, Knockout
  • Mice, Transgenic
  • Nuclear Proteins (physiology)
  • Oxidation-Reduction
  • RGS Proteins (physiology)
  • Receptors, G-Protein-Coupled (metabolism)
  • Transcription Factors (physiology)
  • Transcription, Genetic

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