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27‐Hydroxycholesterol Inhibits Sterol Regulatory Element‐Binding Protein 1 Activation and Hepatic Lipid Accumulation in Mice
Author(s) -
Li Di,
Long Weiqing,
Huang Rong,
Chen Ying,
Xia Min
Publication year - 2018
Publication title -
obesity
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.438
H-Index - 199
eISSN - 1930-739X
pISSN - 1930-7381
DOI - 10.1002/oby.22130
Subject(s) - sterol regulatory element binding protein , lipogenesis , chemistry , steatosis , carbohydrate responsive element binding protein , fatty acid synthase , endoplasmic reticulum , downregulation and upregulation , medicine , endocrinology , lipid metabolism , lipid droplet , biochemistry , sterol , biology , transcription factor , cholesterol , gene
Objective Although 27‐hydroxycholesterol (27‐HC) has been reported as a potent regulator of lipid homeostasis, its role in hepatic lipogenesis remains obscure. The present study was designed to investigate the impact of 27‐HC on sterol regulatory element‐binding protein 1 (SREBP‐1) and hepatic steatosis. Methods In this study, the 27‐HC level in mice was upregulated by overexpressing CYP27A1 or treating primary hepatocytes with 27‐HC, and then the hepatic lipid accumulation was detected. Results 27‐HC inhibited hepatic lipid accumulation and decreased the levels of the mature active form of SREBP‐1. The expression of lipogenic genes, including acetyl coenzyme A carboxylase, fatty acid synthase, stearoyl‐coenzyme A desaturase‐1, and glycerol‐3‐phosphate acyltransferase, were also suppressed after 27‐HC intervention. Furthermore, 27‐HC induced expression of insulin‐induced gene‐2 ( Insig‐2 ), an endoplasmic reticulum protein that prevents SREBP activation, both in vivo and in vitro . The inhibitory effect of 27‐HC on SREBP‐1 activation was absent when Insig‐2 was silenced. Finally, coimmunoprecipitation showed that 27‐HC promoted the binding of Insig‐2 to SREBP‐1. Conclusions These studies demonstrated the suppressive effect of 27‐HC on hepatic lipid accumulation and revealed a novel mechanism by which 27‐HC regulates lipogenesis.