Vitamin D Metabolite, 25-Hydroxyvitamin D, Regulates Lipid Metabolism by Inducing Degradation of SREBP/SCAP

Cell Chem Biol. 2017 Feb 16;24(2):207-217. doi: 10.1016/j.chembiol.2016.12.017. Epub 2017 Jan 26.

Abstract

Sterol regulatory element-binding proteins (SREBPs) are transcription factors that control lipid homeostasis. SREBP activation is regulated by a negative feedback loop in which sterols bind to SREBP cleavage-activating protein (SCAP), an escort protein essential for SREBP activation, or to insulin-induced genes (Insigs) (endoplasmic reticulum [ER] anchor proteins), sequestering the SREBP-SCAP-Insig complex in the ER. We screened a chemical library of endogenous molecules and identified 25-hydroxyvitamin D (25OHD) as an inhibitor of SREBP activation. Unlike sterols and other SREBP inhibitors, 25OHD impairs SREBP activation by inducing proteolytic processing and ubiquitin-mediated degradation of SCAP, thereby decreasing SREBP levels independently of the vitamin D receptor. Vitamin D supplementation has been proposed to reduce the risk of metabolic diseases, but the mechanisms are unknown. The present results suggest a previously unrecognized molecular mechanism of vitamin D-mediated lipid control that might be useful in the treatment of metabolic diseases.

Keywords: SREBP; Vitamin D.

MeSH terms

  • Animals
  • CHO Cells
  • Cells, Cultured
  • Cricetulus
  • Dose-Response Relationship, Drug
  • Down-Regulation / drug effects
  • HEK293 Cells
  • Humans
  • Intracellular Signaling Peptides and Proteins / antagonists & inhibitors*
  • Intracellular Signaling Peptides and Proteins / genetics
  • Intracellular Signaling Peptides and Proteins / metabolism
  • Lipid Metabolism / drug effects*
  • Membrane Proteins / antagonists & inhibitors*
  • Membrane Proteins / genetics
  • Membrane Proteins / metabolism
  • Molecular Conformation
  • RNA, Messenger / drug effects
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Sterol Regulatory Element Binding Proteins / antagonists & inhibitors*
  • Sterol Regulatory Element Binding Proteins / genetics
  • Sterol Regulatory Element Binding Proteins / metabolism
  • Structure-Activity Relationship
  • Vitamin D / analogs & derivatives*
  • Vitamin D / chemistry
  • Vitamin D / metabolism
  • Vitamin D / pharmacology

Substances

  • Intracellular Signaling Peptides and Proteins
  • Membrane Proteins
  • RNA, Messenger
  • SREBP cleavage-activating protein
  • Sterol Regulatory Element Binding Proteins
  • Vitamin D
  • 25-hydroxyvitamin D