GPR146 Deficiency Protects against Hypercholesterolemia and Atherosclerosis

Cell. 2019 Nov 27;179(6):1276-1288.e14. doi: 10.1016/j.cell.2019.10.034.

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.

Keywords: ERK1/2; SREBP2 pathway; atherosclerosis; hypercholesterolemia; orphan G protein-coupled receptor 146.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Atherosclerosis / blood
  • Atherosclerosis / metabolism*
  • Base Sequence
  • Cholesterol / blood
  • Dependovirus / metabolism
  • Extracellular Signal-Regulated MAP Kinases / metabolism
  • Fasting
  • Female
  • Hepatocytes / metabolism
  • Humans
  • Hypercholesterolemia / blood
  • Hypercholesterolemia / metabolism*
  • Lipoproteins, VLDL / metabolism
  • Liver / metabolism
  • Mice
  • Mice, Inbred C57BL
  • RNA, Small Interfering / metabolism
  • Receptors, G-Protein-Coupled / deficiency*
  • Receptors, G-Protein-Coupled / metabolism
  • Receptors, LDL / metabolism
  • Signal Transduction
  • Sterol Regulatory Element Binding Protein 2 / metabolism
  • Triglycerides / blood
  • Up-Regulation

Substances

  • G protein-coupled receptor 146, mouse
  • G-protein coupled receptor 146, human
  • Lipoproteins, VLDL
  • RNA, Small Interfering
  • Receptors, G-Protein-Coupled
  • Receptors, LDL
  • Sterol Regulatory Element Binding Protein 2
  • Triglycerides
  • Cholesterol
  • Extracellular Signal-Regulated MAP Kinases