IR@PKUHSC  > 北京大学基础医学院  > 心血管所
学科主题基础医学
Peroxisome proliferator-activated receptor-delta induces insulin-induced gene-1 and suppresses hepatic lipogenesis in obese diabetic mice
Qin, Xiaomei1,2,3; Xie, Xuefen4; Fan, Yanbo1,2,3; Tian, Jianwei1,2,3; Guan, Youfei1,2,3,4; Wang, Xian1,2,3,4; Zhu, Yi1,2,3,4; Wang, Nanping1,2,3,4
刊名HEPATOLOGY
2008-08-01
DOI10.1002/hep.22334
48期:2页:432-441
收录类别SCI
文章类型Article
WOS标题词Science & Technology
类目[WOS]Gastroenterology & Hepatology
研究领域[WOS]Gastroenterology & Hepatology
关键词[WOS]VASCULAR ENDOTHELIAL-CELLS ; ADENOVIRUS-MEDIATED OVEREXPRESSION ; INTERCELLULAR-ADHESION MOLECULE-1 ; ELEMENT-BINDING PROTEIN ; FATTY LIVER-DISEASE ; PPAR-DELTA ; METABOLIC SYNDROME ; C-JUN ; CHOLESTEROL-SYNTHESIS ; ADIPOSE-TISSUE
英文摘要

Primary nonalcoholic fatty liver disease is one of the most common forms of chronic liver diseases and is associated with insulin-resistant states such as diabetes and obesity. Recent work has revealed potential implications of peroxisome proliferator-activated receptor-delta (PPAR delta) in lipid homeostasis and insulin resistance. In this study, we examined the effect of PPAR delta on sterol regulatory element-binding protein-1 (SREBP-1), a pivotal transcription factor controlling lipogenesis in hepatocytes. Treatment with GW0742, the PPAR delta agonist, or overexpression of PPAR delta markedly reduced intracellular lipid accumulation. GW0742 and PPAR delta overexpression in hepatocytes induced the expression of insulin-induced gene-1 (Insig-1), an endoplasmic reticulum protein braking SREBP activation, at both the mRNA and the protein levels. PPAR delta inhibited the proteolytic processing of SREBP-1 into the mature active form, thereby suppressing the expression of the lipogenic genes fatty acid synthase, stearyl CoA desaturase-1, and acetyl coenzyme A carboxylase. Our results revealed a direct binding of PPAR delta to a noncanonical peroxisome proliferator responsive element motif upstream of the transcription initiation site of human Insig-1. The disruption of this site diminished the induction of Insig-1, which suggested that Insig-1 is a direct PPAR delta target gene in hepatocytes. Knockdown of endogenous Insig-1 attenuated the suppressive effect of GW0742 on SREBP-1 and its target genes, indicating PPAR delta inhibited SREBP-1 activation via induction of Insig-1. Furthermore, overexpression of PPAR delta by intravenous infection with the PPAR delta adenovirus induced the expression of Insig-1, suppressed SREBP-1 activation, and, consequently, ameliorated hepatic steatosis in obese db/db mice. Conclusion: Our study reveals a novel mechanism by which PPAR delta regulates lipogenesis, suggesting potential therapeutic applications of PPAR delta modulators in obesity and type 2 diabetes, as well as related steatotic liver diseases.

语种英语
WOS记录号WOS:000258247400010
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被引频次:98[WOS]   [WOS记录]     [WOS相关记录]
文献类型期刊论文
条目标识符http://ir.bjmu.edu.cn/handle/400002259/67593
专题北京大学基础医学院_心血管所
北京大学基础医学院
作者单位1.Peking Univ, Hlth Sci Ctr, Inst Cardiovasc Sci, Beijing 100083, Peoples R China
2.Peking Univ, Hlth Sci Ctr, Minist Educ, Key Lab Cardiovasc Sci, Beijing 100083, Peoples R China
3.Peking Univ, Hlth Sci Ctr, Ctr Diabet, Beijing 100083, Peoples R China
4.Peking Univ, Hlth Sci Ctr, Dept Physiol & Pathophysiol, Beijing 100083, Peoples R China
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GB/T 7714
Qin, Xiaomei,Xie, Xuefen,Fan, Yanbo,et al. Peroxisome proliferator-activated receptor-delta induces insulin-induced gene-1 and suppresses hepatic lipogenesis in obese diabetic mice[J]. HEPATOLOGY,2008,48(2):432-441.
APA Qin, Xiaomei.,Xie, Xuefen.,Fan, Yanbo.,Tian, Jianwei.,Guan, Youfei.,...&Wang, Nanping.(2008).Peroxisome proliferator-activated receptor-delta induces insulin-induced gene-1 and suppresses hepatic lipogenesis in obese diabetic mice.HEPATOLOGY,48(2),432-441.
MLA Qin, Xiaomei,et al."Peroxisome proliferator-activated receptor-delta induces insulin-induced gene-1 and suppresses hepatic lipogenesis in obese diabetic mice".HEPATOLOGY 48.2(2008):432-441.
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