Peroxisome proliferator-activated receptor-delta induces insulin-induced gene-1 and suppresses hepatic lipogenesis in obese diabetic mice.
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 (PPARdelta) in lipid homeostasis and insulin resistance. In this study, we examined the effect of PPARdelta on sterol regulatory element-binding protein-1 (SREBP-1), a pivotal transcription factor controlling lipogenesis in hepatocytes. Treatment with GW0742, the PPARdelta agonist, or overexpression of PPARdelta markedly reduced intracellular lipid accumulation. GW0742 and PPARdelta 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. PPARdelta 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 PPARdelta 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 PPARdelta target gene in hepatocytes. Knockdown of endogenous Insig-1 attenuated the suppressive effect of GW0742 on SREBP-1 and its target genes, indicating PPARdelta inhibited SREBP-1 activation via induction of Insig-1. Furthermore, overexpression of PPARdelta by intravenous infection with the PPARdelta adenovirus induced the expression of Insig-1, suppressed SREBP-1 activation, and, consequently, ameliorated hepatic steatosis in obese db/db mice.


CONCLUSIONS
Our study reveals a novel mechanism by which PPARdelta regulates lipogenesis, suggesting potential therapeutic applications of PPARdelta modulators in obesity and type 2 diabetes, as well as related steatotic liver diseases.
Qin
Xiaomei
X
Institute of Cardiovascular Science and Key Laboratory of Cardiovascular Science of Ministry of Education, Peking University Health Science Center, Beijing, China.
Xie
Xuefen
X
Fan
Yanbo
Y
Tian
Jianwei
J
Guan
Youfei
Y
Wang
Xian
X
Zhu
Yi
Y
Wang
Nanping
N
D000818:Animals; D045744:Cell Line, Tumor; D048909:Diabetes Complications; D003920:Diabetes Mellitus / Q000235:genetics / Q000378:metabolism*; D022781:Hepatocytes / Q000378:metabolism; D006801:Humans; D050155:Lipogenesis / Q000187:drug effects*; D008099:Liver / Q000378:metabolism*; D008297:Male; D008565:Membrane Proteins / Q000096:biosynthesis* / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D008820:Mice, Obese; D009765:Obesity / Q000150:complications / Q000378:metabolism*; D047494:PPAR delta / Q000494:pharmacology*; D020025:Peroxisome Proliferators; D034741:RNA, Small Interfering / Q000494:pharmacology; D020218:Response Elements; D051780:Sterol Regulatory Element Binding Protein 1 / Q000037:antagonists & inhibitors; D013844:Thiazoles / Q000494:pharmacology; D014162:Transfection; D010636:Phenols; D013438:Sulfhydryl Compounds
D008565:Membrane Proteins; D047494:PPAR delta; D020025:Peroxisome Proliferators; D034741:RNA, Small Interfering; D051780:Sterol Regulatory Element Binding Protein 1; D013844:Thiazoles; C506119:Insig1 protein, mouse; C497388:Srebf1 protein, mouse; C479979:(4-(((2-(3-fluoro-4-(trifluoromethyl)phenyl)-4-methyl-1,3-thiazol-5-yl)methyl)sulfanyl)-2-methylphenoxy)acetic acid; D010636:Phenols; D013438:Sulfhydryl Compounds