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

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

Author information

1
Institute for Integrated Cell-Material Sciences (WPI-iCeMS), Kyoto University, Uji, Kyoto 611-0011, Japan; Institute for Chemical Research, Kyoto University, Uji, Kyoto 611-0011, Japan.
2
Institute for Chemical Research, Kyoto University, Uji, Kyoto 611-0011, Japan.
3
Department of Biotechnology and Life Science, Tokyo University of Agriculture and Technology, Koganei, Tokyo 184-8588, Japan.
4
Institute for Integrated Cell-Material Sciences (WPI-iCeMS), Kyoto University, Uji, Kyoto 611-0011, Japan.
5
Division of Metabolic Medicine, Research Center for Advanced Science and Technology (RCAST), The University of Tokyo, Tokyo 153-8904, Japan; The Translational Systems Biology and Medicine Initiative, Center for Disease Biology and Integrative Medicine, Faculty of Medicine, University of Tokyo, Tokyo 113-8655, Japan.
6
Department of Biotechnology and Life Science, Tokyo University of Agriculture and Technology, Koganei, Tokyo 184-8588, Japan; CREST, AMED. Electronic address: knaga@cc.tuat.ac.jp.
7
Institute for Integrated Cell-Material Sciences (WPI-iCeMS), Kyoto University, Uji, Kyoto 611-0011, Japan; Institute for Chemical Research, Kyoto University, Uji, Kyoto 611-0011, Japan; CREST, AMED. Electronic address: uesugi@scl.kyoto-u.ac.jp.

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

PMID:
28132894
DOI:
10.1016/j.chembiol.2016.12.017
[Indexed for MEDLINE]
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