Vitamin D Metabolite, 25-Hydroxyvitamin D, Regulates Lipid Metabolism by Inducing Degradation of SREBP/SCAP. Issue 2 (16th February 2017)

• Record Type: Journal Article
• Authors: Asano, Lisa; Watanabe, Mizuki; Ryoden, Yuta; Usuda, Kousuke; Yamaguchi, Takuya; Khambu, Bilon; Takashima, Megumi; Sato, Shin-ichi; Sakai, Juro; Nagasawa, Kazuo; Uesugi, Motonari
• Is Part Of: Cell chemical biology. Volume 24:Issue 2(2017)
• Page Start: 207
• Page End: 217
• Publication Date: 2017-02-16
• Subjects: SREBP -- Vitamin D; Biochemistry -- Periodicals; 572.05
• DOI: 10.1016/j.chembiol.2016.12.017
• Languages: English
• ISSNs: 2451-9456

Abstract

Summary: 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. Graphical Abstract: Highlights: 25-Hydroxyvitamin D (25OHD) is an endogenous inhibitor of SREBP 25OHD induces proteolytic processing and ubiquitin-mediated degradation of SCAP The mechanism provides a potential therapeutic approach for lipid disorders Abstract : Asano et al. identified 25-hydroxyvitamin D (25OHD) as a new endogenous inhibitor of SREBP. 25OHD impairs SREBP activation by inducing proteolytic processing and ubiquitin-mediated degradation of SCAP, implying a new opportunity for pharmacological control of SREBP/SCAP.