title: Inhibition of SREBP by a small molecule, betulin, improves hyperlipidemia and insulin resistance and reduces atherosclerotic plaques.
abstract: Sterol regulatory element-binding proteins (SREBPs) are major transcription factors activating the expression of genes involved in biosynthesis of cholesterol, fatty acid and triglyceride. In this study, we identified a small molecule, betulin, that specifically inhibited the maturation of SREBP by inducing interaction of SREBP cleavage activating protein (SCAP) and Insig. Inhibition of SREBP by betulin decreased the biosynthesis of cholesterol and fatty acid. In vivo, betulin ameliorated diet-induced obesity, decreased the lipid contents in serum and tissues, and increased insulin sensitivity. Furthermore, betulin reduced the size and improved the stability of atherosclerotic plaques. Our study demonstrates that inhibition SREBP pathway can be employed as a therapeutic strategy to treat metabolic diseases including type II diabetes and atherosclerosis. Betulin, which is abundant in birch bark, could be a leading compound for development of drugs for hyperlipidemia.
authors.affiliation: The State Key Laboratory of Molecular Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 320 Yue-Yang Road, Shanghai 200031, China.
authors.forename: Jing-Jie
authors.initials: JJ
authors.lastname: Tang
authors.forename: Jia-Gui
authors.initials: JG
authors.lastname: Li
authors.forename: Wei
authors.initials: W
authors.lastname: Qi
authors.forename: Wen-Wei
authors.initials: WW
authors.lastname: Qiu
authors.forename: Pei-Shan
authors.initials: PS
authors.lastname: Li
authors.forename: Bo-Liang
authors.initials: BL
authors.lastname: Li
authors.forename: Bao-Liang
authors.initials: BL
authors.lastname: Song
mesh_terms: D000818:Animals; D002784:Cholesterol / Q000096:biosynthesis / Q000235:genetics; D015536:Down-Regulation; D004734:Energy Metabolism / Q000187:drug effects; D005227:Fatty Acids / Q000096:biosynthesis; D006801:Humans; D006949:Hyperlipidemias / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D007333:Insulin Resistance / Q000502:physiology*; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D050356:Lipid Metabolism; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009765:Obesity / Q000188:drug therapy; D058226:Plaque, Atherosclerotic / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D051779:Sterol Regulatory Element Binding Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D014315:Triterpenes / Q000032:analysis / Q000737:chemistry / Q000494:pharmacology*; D000094062:Betulinic Acid
chemical_list: D002784:Cholesterol; D005227:Fatty Acids; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D051779:Sterol Regulatory Element Binding Proteins; D014315:Triterpenes; C102196:SREBP cleavage-activating protein; C002503:betulin; D000094062:Betulinic Acid