title: Endoplasmic reticulum-tethered transcription factor cAMP responsive element-binding protein, hepatocyte specific, regulates hepatic lipogenesis, fatty acid oxidation, and lipolysis upon metabolic stress in mice.
abstract: cAMP responsive element-binding protein, hepatocyte specific (CREBH), is a liver-specific transcription factor localized in the endoplasmic reticulum (ER) membrane. Our previous work demonstrated that CREBH is activated by ER stress or inflammatory stimuli to induce an acute-phase hepatic inflammation. Here, we demonstrate that CREBH is a key metabolic regulator of hepatic lipogenesis, fatty acid (FA) oxidation, and lipolysis under metabolic stress. Saturated FA, insulin signals, or an atherogenic high-fat diet can induce CREBH activation in the liver. Under the normal chow diet, CrebH knockout mice display a modest decrease in hepatic lipid contents, but an increase in plasma triglycerides (TGs). After having been fed an atherogenic high-fat (AHF) diet, massive accumulation of hepatic lipid metabolites and significant increase in plasma TG levels were observed in the CrebH knockout mice. Along with the hypertriglyceridemia phenotype, the CrebH null mice displayed significantly reduced body-weight gain, diminished abdominal fat, and increased nonalcoholic steatohepatitis activities under the AHF diet. Gene-expression analysis and chromatin-immunoprecipitation assay indicated that CREBH is required to activate the expression of the genes encoding functions involved in de novo lipogenesis, TG and cholesterol biosynthesis, FA elongation and oxidation, lipolysis, and lipid transport. Supporting the role of CREBH in lipogenesis and lipolysis, forced expression of an activated form of CREBH protein in the liver significantly increases accumulation of hepatic lipids, but reduces plasma TG levels in mice.
  
  
  CONCLUSIONS
  All together, our study shows that CREBH plays a key role in maintaining lipid homeostasis by regulating the expression of the genes involved in hepatic lipogenesis, FA oxidation, and lipolysis under metabolic stress. The identification of CREBH as a stress-inducible metabolic regulator has important implications in the understanding and treatment of metabolic disease.
authors.affiliation: Center for Molecular Medicine and Genetics,The Wayne State University School of Medicine, Detroit, MI 48201, USA.
authors.forename: Chunbin
authors.initials: C
authors.lastname: Zhang
authors.forename: Guohui
authors.initials: G
authors.lastname: Wang
authors.forename: Ze
authors.initials: Z
authors.lastname: Zheng
authors.forename: Krishna Rao
authors.initials: KR
authors.lastname: Maddipati
authors.forename: Xuebao
authors.initials: X
authors.lastname: Zhang
authors.forename: Gregory
authors.initials: G
authors.lastname: Dyson
authors.forename: Paul
authors.initials: P
authors.lastname: Williams
authors.forename: Stephen A
authors.initials: SA
authors.lastname: Duncan
authors.forename: Randal J
authors.initials: RJ
authors.lastname: Kaufman
authors.forename: Kezhong
authors.initials: K
authors.lastname: Zhang
mesh_terms: D000818:Animals; D017362:Cyclic AMP Response Element-Binding Protein / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D004041:Dietary Fats / Q000009:adverse effects / Q000494:pharmacology; D004195:Disease Models, Animal; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D005227:Fatty Acids / Q000378:metabolism*; D005234:Fatty Liver / Q000209:etiology / Q000235:genetics / Q000503:physiopathology; D006487:Hemostasis / Q000187:drug effects / Q000502:physiology; D015228:Hypertriglyceridemia / Q000209:etiology / Q000235:genetics / Q000503:physiopathology; D050155:Lipogenesis / Q000187:drug effects / Q000502:physiology*; D008066:Lipolysis / Q000187:drug effects / Q000502:physiology*; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010084:Oxidation-Reduction; D013312:Stress, Physiological / Q000187:drug effects / Q000502:physiology*; D014280:Triglycerides / Q000097:blood
chemical_list: C500051:Creb3l3 protein, mouse; D017362:Cyclic AMP Response Element-Binding Protein; D004041:Dietary Fats; D005227:Fatty Acids; D014280:Triglycerides
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