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 ␣-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 ␤-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 GPCRstimulated fatty acid oxidation in hepatocytes.Body weight homeostasis is maintained, in part, by complex communication between G protein-coupled receptors (GPCRs) 5 localized in the brain and in the periphery. Long term and short term satiety signals are integrated to create a dynamic equilibrium between energy expenditure and food intake.The activation cycle of heterotrimeric G proteins revolves around receptor-catalyzed guanine nucleotide exchange on the G␣ subunit; the G␣ GDP ␤␥ heterotrimer is inactive, whereas hormone binding to receptor catalyzes formation of active G␣ GTP (1). RGS proteins are GTPase-activating proteins (GAPs) for G i -and G q/11 -class ␣-subunits and can terminate signaling by restoring the inactive G␣ GDP ␤␥ heterotrimer, thereby uncoupling hormone-bound receptor from effector protein activation (2-4). An important complexity of G protein signaling is that both G␣ GTP and free G␤␥ subunits can independently regulate the production of second messengers by effector proteins. RGS proteins can integrate and coordinate responses to separate G␣ and G␤␥ signals to generate an emergent property, such as RGS-mediated Ca 2ϩ oscillations evoked by G␣ q/11 -coupled agonists (5-8).Given that Rgs mRNAs were up-regulated by GPCR agonists controlling mating responses and nutrient sensing in fungi (9 -11), we hypothesized that Rgs expression could be utilized as a marker for unknown G i -or G q/11 -mediated signal transduction in mammalian physiology. To explore novel G protein function in liver, we surveyed differential regulation of Rgs genes in liver of fasted and refed wild type mice (12). Interestingly, of the 21 Rgs genes, only Rgs16 mRNA was diurnally express...

Significant lethality following liver resection in A20 heterozygous knockout mice uncovers a key role for A20 in liver regeneration

“…Akin A20 HET, hepatocyte-specific overexpression of RGS16 also increases intrahepatic TG levels and provokes regenerationdefective fatty livers. 52 Altogether, our results establish A20 as an integral physiologic regulator of LR by exposing that mere A20 haploinsufficiency causes defective LR through the additive/ amplifying contribution of heightened p21 protein levels and deregulated lipid metabolism. Recently discovered single nucleotide polymorphisms (SNPs) in the A20/TNFAIP3 locus that correspond with numerous autoimmune and inflammatory diseases highlight the clinical implication of these data.…”

Open Chromatin Profiling in Mice Livers Reveals Unique Chromatin Variations Induced by High Fat Diet

“…5B), which has three eQTL SNPs overlapping a D2 HF-specific FAIRE site ϳ30 kb upstream of the transcription start site. Regulators of G protein signaling (RGS) proteins help control hepatic lipid homeostasis, and Rgs16 has been shown to signal for glucose production for inhibition of fatty acid oxidation (41,42).…”

Mice without MacroH2A Histone Variants

“…These results reinforce our previous finding that macroH2A.1 has a role in regulating metabolism-related genes, especially genes related to lipid metabolism (23,24). Two of the other 5 new genes also have a clear connection to lipid metabolism: Lepr (1.9-fold increase) encodes the receptor for leptin, an adipokine that has a central role in energy homeostasis (37), and Rgs16 (2.3-fold increase) encodes a GTPase-activating protein that can regulate fatty acid and glucose metabolism in the liver (38). The proteins encoded by the other 3 genes do not have any obvious connection to lipid metabolism: Sdf2l1 (2.6-fold increase) appears to be a subunit of an endoplasmic reticulum chaperone complex, Vtcn1 (2.5-fold increase) is a T-cell activation inhibitor, and Hamp2 (2.4-fold decrease) is thought to be an antimicrobial peptide that also regulates iron uptake.…”