title: Histone modifications in FASN modulated by sterol regulatory element-binding protein 1c and carbohydrate responsive-element binding protein under insulin stimulation are related to NAFLD.
abstract: Non-alcoholic fatty liver disease (NAFLD) and its causal factors of hepatic insulin resistance (IR) and type 2 diabetes are rapidly growing worldwide. Developing new therapeutic methods for these conditions requires a comprehensive understanding between hepatic lipid metabolism and IR. Sterol regulatory element-binding transcription factor 1c (SREBP-1c) and carbohydrate responsive-element binding protein (ChREBP) are the major regulators of fatty acid synthase (FASN), a key enzyme of de novo fatty acid synthesis. They are induced by insulin, which directly binds to the sterol regulatory elements (SRE) or carbohydrate-responsive elements (ChORE) of the FASN promoter to induce its expression. The insulin pathway involved in NAFLD has well studied, but the role of histone modification in NAFLD is just beginning to be investigated, and there is minimal data regarding its involvement. In the current study, we investigated histone modifications in FASN under insulin stimulation. H3K4 hypertrimethylation and H3, H4 hyperacetylation in the FASN promoter was found in HepG2 cells and primary hepatocytes following insulin stimulation. We also found that insulin treatment induced the transcription factor SREBP-1c, ChREBP and could accelerate FASN expression by enhancing SREBP-1c, SRE, and ChREBP ChORE binding and inducing H3, H4 hyperacetylation at SRE, ChORE, or transcription start site (TSS) regions of the FASN promoter in hepatocellular carcinoma cell line (HepG2) and primary hepatocytes. Finally, histone acetylation could influence FASN expression by impairing SREBP-1c SRE and ChREBP ChORE binding.
authors.affiliation: Department of Gastroenterology, 2nd Affiliated Hospital of Chongqing Medical University, Chongqing, 400010, PR China.
authors.forename: Xuan
authors.initials: X
authors.lastname: Du
authors.affiliation: Department of Gastroenterology, 2nd Affiliated Hospital of Chongqing Medical University, Chongqing, 400010, PR China.
authors.forename: Can
authors.initials: C
authors.lastname: Cai
authors.affiliation: Department of Gastroenterology, 2nd Affiliated Hospital of Chongqing Medical University, Chongqing, 400010, PR China.
authors.forename: Jialing
authors.initials: J
authors.lastname: Yao
authors.affiliation: Department of Gastroenterology, 2nd Affiliated Hospital of Chongqing Medical University, Chongqing, 400010, PR China.
authors.forename: Youping
authors.initials: Y
authors.lastname: Zhou
authors.affiliation: Department of Gastroenterology, 2nd Affiliated Hospital of Chongqing Medical University, Chongqing, 400010, PR China.
authors.forename: Huihong
authors.initials: H
authors.lastname: Yu
authors.affiliation: Department of Gastroenterology, 2nd Affiliated Hospital of Chongqing Medical University, Chongqing, 400010, PR China. Electronic address: shenwei315@126.com.
authors.forename: Wei
authors.initials: W
authors.lastname: Shen
mesh_terms: D000107:Acetylation; D000818:Animals; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / Q000378:metabolism*; D054890:Fatty Acid Synthase, Type I / Q000378:metabolism*; D005260:Female; D056945:Hep G2 Cells; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism; D006657:Histones / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007328:Insulin / Q000378:metabolism / Q000494:pharmacology; D008745:Methylation; D065626:Non-alcoholic Fatty Liver Disease / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D017207:Rats, Sprague-Dawley; D012045:Regulatory Sequences, Nucleic Acid; D051780:Sterol Regulatory Element Binding Protein 1 / Q000378:metabolism*; D024363:Transcription Initiation Site
chemical_list: D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D006657:Histones; D007328:Insulin; C116385:MLXIPL protein, human; C497389:Srebf1 protein, rat; D051780:Sterol Regulatory Element Binding Protein 1; C518729:FASN protein, human; D054890:Fatty Acid Synthase, Type I
keywords: ChREBP; Hepatocyte steatosis; Histone modification; IR; NAFLD; SREBP-1c