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New Key Publication:GPR146 Deficiency Protects against Hypercholesterolemia and Atherosclerosis

27 November 2019
Cell2019
Cell2019
  • Yu H
  • Rimbert A
  • Palmer AE
  • Toyohara T
  • Xia Y
  • Xia F
  • Ferreira LMR
  • Chen Z
  • Chen T
  • Loaiza N
  • Horwitz NB
  • Kacergis MC
  • Zhao L
  • BIOS Consortium
  • Soukas AA
  • Kuivenhoven JA
  • Kathiresan S
  • Cowan CA

Abstract: Although human genetic studies have implicated many susceptible genes associated with plasma lipid levels, their physiological and molecular functions are not fully characterized. Here we demonstrate that orphan G protein-coupled receptor 146 (GPR146) promotes activity of hepatic sterol regulatory element binding protein 2 (SREBP2) through activation of the extracellular signal-regulated kinase (ERK) signaling pathway, thereby regulating hepatic very low-density lipoprotein (VLDL) secretion, and subsequently circulating low-density lipoprotein cholesterol (LDL-C) and triglycerides (TG) levels.

Remarkably, GPR146 deficiency reduces plasma cholesterol levels substantially in both wild-type and LDL receptor (LDLR)-deficient mice. Finally, aortic atherosclerotic lesions are reduced by 90% and 70%, respectively, in male and female LDLR-deficient mice upon GPR146 depletion.

Taken together, these findings outline a regulatory role for the GPR146/ERK axis in systemic cholesterol metabolism and suggest that GPR146 inhibition could be an effective strategy to reduce plasma cholesterol levels and atherosclerosis.

Last modified:27 December 2019 9.37 p.m.

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