title: Inhibition of SREBP transcriptional activity by a boron-containing compound improves lipid homeostasis in diet-induced obesity.
abstract: Dysregulation of lipid homeostasis is intimately associated with obesity, type 2 diabetes, and cardiovascular diseases. Sterol regulatory-element binding proteins (SREBPs) are the master regulators of lipid biosynthesis. Previous studies have shown that the conserved transcriptional cofactor Mediator complex is critically required for the SREBP transcriptional activity, and recruitment of the Mediator complex to the SREBP transactivation domains (TADs) is through the MED15-KIX domain. Recently, we have synthesized several boron-containing small molecules. Among these novel compounds, BF175 can specifically block the binding of MED15-KIX to SREBP1a-TAD in vitro, resulting in an inhibition of the SREBP transcriptional activity and a decrease of SREBP target gene expression in cultured hepatocytes. Furthermore, BF175 can improve lipid homeostasis in the mouse model of diet-induced obesity. Compared with the control, BF175 treatment decreased the expression of SREBP target genes in mouse livers and decreased hepatic and blood levels of lipids. These results suggest that blocking the interaction between SREBP-TADs and the Mediator complex by small molecules may represent a novel approach for treating diseases with aberrant lipid homeostasis.
authors.affiliation: Division of Endocrinology, Department of Medicine, Albert Einstein College of Medicine, Bronx, NYDepartment of Developmental & Molecular Biology, Albert Einstein College of Medicine, Bronx, NYDepartment of Nuclear Medicine, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, People's Republic of China.
authors.forename: Xiaoping
authors.initials: X
authors.lastname: Zhao
authors.affiliation: Division of Endocrinology, Department of Medicine, Albert Einstein College of Medicine, Bronx, NYDepartment of Developmental & Molecular Biology, Albert Einstein College of Medicine, Bronx, NY.
authors.lastname: Xiaoli
authors.affiliation: Division of Endocrinology, Department of Medicine, Albert Einstein College of Medicine, Bronx, NY.
authors.forename: Haihong
authors.initials: H
authors.lastname: Zong
authors.affiliation: Division of Endocrinology, Department of Medicine, Albert Einstein College of Medicine, Bronx, NYDepartment of Developmental & Molecular Biology, Albert Einstein College of Medicine, Bronx, NY.
authors.forename: Arian
authors.initials: A
authors.lastname: Abdulla
authors.affiliation: Division of Endocrinology, Department of Medicine, Albert Einstein College of Medicine, Bronx, NY.
authors.forename: Ellen S T
authors.initials: ES
authors.lastname: Yang
authors.affiliation: Department of Molecular and Cellular Medicine, College of Medicine, Texas A&M Health Science Center, College Station, TX.
authors.forename: Qun
authors.initials: Q
authors.lastname: Wang
authors.affiliation: Department of Molecular and Cellular Medicine, College of Medicine, Texas A&M Health Science Center, College Station, TX.
authors.forename: Jun-Yuan
authors.initials: JY
authors.lastname: Ji
authors.affiliation: Division of Endocrinology, Department of Medicine, Albert Einstein College of Medicine, Bronx, NYDepartment of Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, NY.
authors.forename: Jeffrey E
authors.initials: JE
authors.lastname: Pessin
authors.affiliation: Division of Hematology and Oncology, Department of Medicine, University of Kansas Medical Center, Kansas City, KS.
authors.forename: Bhaskar C
authors.initials: BC
authors.lastname: Das
authors.affiliation: Division of Endocrinology, Department of Medicine, Albert Einstein College of Medicine, Bronx, NYDepartment of Developmental & Molecular Biology, Albert Einstein College of Medicine, Bronx, NY fajun.yang@einstein.yu.edu.
authors.forename: Fajun
authors.initials: F
authors.lastname: Yang
mesh_terms: D000818:Animals; D001896:Boron Compounds / Q000494:pharmacology*; D001897:Boronic Acids / Q000494:pharmacology*; D002478:Cells, Cultured; D004032:Diet / Q000009:adverse effects; D004331:Drosophila melanogaster; D004353:Drug Evaluation, Preclinical; D057809:HEK293 Cells; D056945:Hep G2 Cells; D006706:Homeostasis / Q000187:drug effects / Q000235:genetics; D006801:Humans; D050356:Lipid Metabolism / Q000187:drug effects* / Q000235:genetics; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009765:Obesity / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D051779:Sterol Regulatory Element Binding Proteins / Q000037:antagonists & inhibitors*; D013267:Stilbenes / Q000494:pharmacology*; D015533:Transcriptional Activation / Q000187:drug effects*
chemical_list: C000591244:BF175 compound; D001896:Boron Compounds; D001897:Boronic Acids; D051779:Sterol Regulatory Element Binding Proteins; D013267:Stilbenes