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

被引：143

作者：

Asano, Lisa ^{[1
,2
]}

Watanabe, Mizuki ^{[1
,2
]}

Ryoden, Yuta ^{[2
]}

Usuda, Kousuke ^{[3
]}

Yamaguchi, Takuya ^{[3
]}

Khambu, Bilon ^{[1
]}

Takashima, Megumi ^{[1
]}

Sato, Shin-ichi ^{[1
]}

Sakai, Juro ^{[4
,5
]}

Nagasawa, Kazuo ^{[3
,6
]}

Uesugi, Motonari ^{[1
,2
,6
]}

机构：

[1] Kyoto Univ, Inst Integrated Cell Mat Sci WPI iCeMS, Uji, Kyoto 6110011, Japan

[2] Kyoto Univ, Inst Chem Res, Uji, Kyoto 6110011, Japan

[3] Tokyo Univ Agr & Technol, Dept Biotechnol & Life Sci, Koganei, Tokyo 1848588, Japan

[4] Univ Tokyo, Div Metab Med, Res Ctr Adv Sci & Technol, Tokyo 1538904, Japan

[5] Univ Tokyo, Ctr Dis Biol & Integrat Med, Translat Syst Biol & Med Initiat, Fac Med, Tokyo 1138655, Japan

[6] CREST, AMED, Uji, Kyoto, Japan

来源：

CELL CHEMICAL BIOLOGY | 2017年 / 24卷 / 02期

关键词：

CLEAVAGE-ACTIVATING PROTEIN; STEROL-SENSING DOMAIN; HMG COA REDUCTASE; FATTY LIVER-DISEASE; ENDOPLASMIC-RETICULUM; CHOLESTEROL-METABOLISM; UBIQUITIN LIGASE; SMALL-MOLECULE; D DEFICIENCY; D-RECEPTOR;

D O I：

10.1016/j.chembiol.2016.12.017

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

070307 [化学生物学]; 071010 [生物化学与分子生物学];

摘要：

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 molecularmechanism of vitamin D-mediated lipid control that might be useful in the treatment of metabolic diseases.

引用

页码：207 / 217

页数：11

共 46 条

[1]

Cholesterol and 25-hydroxycholesterol inhibit activation of SREBPs by different mechanisms, both involving SCAP and insigs [J].