title: cAMP response element binding protein H mediates fenofibrate-induced suppression of hepatic lipogenesis.
abstract: OBJECTIVE
  Fenofibrate is a drug used to treat hyperlipidaemia that works by inhibiting hepatic triacylglycerol synthesis. Sterol regulatory element binding protein-1c (SREBP-1c) is a major regulator of the expression of genes involved in hepatic triacylglycerol synthesis. In addition, endoplasmic reticulum (ER)-bound transcription factor families are involved in the control of various metabolic pathways. Here, we show a novel function for an ER-bound transcription factor, cAMP response element binding protein H (CREBH), in fenofibrate-mediated inhibition of hepatic lipogenesis.
  
  
  METHODS
  The effects of fenofibrate and adenovirus-mediated Crebh (also known as Creb313) overexpression (Ad-Crebh) on hepatic SREBP-1c production and lipogenesis in vitro and in vivo were investigated. We also examined whether downregulation of endogenous hepatic Crebh by small interfering (si)RNA restores the fenofibrate effect on hepatic lipogenesis and SREBP-1c production. Finally, we examined the mechanism by which CREBH inhibits hepatic SREBP-1c production.
  
  
  RESULTS
  Fasting and fenofibrate treatment induced CREBH production and decreased SREBP-1c levels. Indeed, Ad-Crebh inhibited insulin- and liver X receptor agonist TO901317-induced Srebp-1c (also known as Srebf1) mRNA expression in cultured hepatocytes. Moreover, increased production of CREBH in the liver of mice following tail-vein injection of Ad-Crebh inhibited high-fat diet-induced hepatic steatosis through inhibition of Srebp-1c expression. The inhibition of endogenous Crebh expression by siRNA restored fenofibrate-induced suppression of Srebp-1c expression and hepatic lipid accumulation both in vitro and in vivo.
  
  
  CONCLUSIONS
  These results show that fenofibrate decreases hepatic lipid synthesis through induction of CREBH. This study suggests CREBH as a novel negative regulator of SREBP-1c production and hepatic lipogenesis.
authors.affiliation: Division of Endocrinology and Metabolism, Department of Internal Medicine, Research Institute of Aging and Metabolism, WCU Program, Kyungpook National University School of Medicine, Daegu, South Korea.
authors.forename: A-K
authors.initials: AK
authors.lastname: Min
authors.forename: J Y
authors.initials: JY
authors.lastname: Jeong
authors.forename: Y
authors.initials: Y
authors.lastname: Go
authors.forename: Y-K
authors.initials: YK
authors.lastname: Choi
authors.forename: Y-D
authors.initials: YD
authors.lastname: Kim
authors.forename: I-K
authors.initials: IK
authors.lastname: Lee
authors.forename: K-G
authors.initials: KG
authors.lastname: Park
mesh_terms: D000818:Animals; D002460:Cell Line; D045744:Cell Line, Tumor; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism*; D005234:Fatty Liver / Q000378:metabolism; D011345:Fenofibrate / Q000494:pharmacology*; D056945:Hep G2 Cells; D006801:Humans; D050155:Lipogenesis / Q000187:drug effects*; D008099:Liver / Q000187:drug effects* / Q000378:metabolism*; D051379:Mice; D051381:Rats; D051780:Sterol Regulatory Element Binding Protein 1 / Q000378:metabolism
chemical_list: D017362:Cyclic AMP Response Element-Binding Protein; D051780:Sterol Regulatory Element Binding Protein 1; D011345:Fenofibrate