title: Transcriptional regulation of apolipoprotein A-IV by the transcription factor CREBH.
abstract: cAMP responsive element-binding protein H (CREBH) is an endoplasmic reticulum (ER) anchored transcription factor that is highly expressed in the liver and small intestine and implicated in nutrient metabolism and proinflammatory response. ApoA-IV is a glycoprotein secreted primarily by the intestine and to a lesser degree by the liver. ApoA-IV expression is suppressed in CREBH-deficient mice and strongly induced by enforced expression of the constitutively active form of CREBH, indicating that CREBH is the major transcription factor regulating Apoa4 gene expression. Here, we show that CREBH directly controls Apoa4 expression through two tandem CREBH binding sites (5'-CCACGTTG-3') located on the promoter, which are conserved between human and mouse. Chromatin immunoprecipitation and electrophoretic mobility-shift assays demonstrated specific association of CREBH with the CREBH binding sites. We also demonstrated that a substantial amount of CREBH protein was basally processed to the active nuclear form in normal mouse liver, which was further increased in steatosis induced by high-fat diet or fasting, increasing apoA-IV expression. However, we failed to find significant activation of CREBH in response to ER stress, arguing against the critical role of CREBH in ER stress response.
authors.affiliation: Department of Pathology and Laboratory Medicine, Weill Cornell Medical College, New York, NY.
authors.forename: Xu
authors.initials: X
authors.lastname: Xu
authors.forename: Jong-Gil
authors.initials: JG
authors.lastname: Park
authors.forename: Jae-Seon
authors.initials: JS
authors.lastname: So
authors.forename: Kyu Yeon
authors.initials: KY
authors.lastname: Hur
authors.forename: Ann-Hwee
authors.initials: AH
authors.lastname: Lee
mesh_terms: D000818:Animals; D001054:Apolipoproteins A / Q000235:genetics*; D001483:Base Sequence; D001665:Binding Sites; D002460:Cell Line; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism*; D005234:Fatty Liver / Q000235:genetics; D005786:Gene Expression Regulation; D022781:Hepatocytes / Q000378:metabolism; D006801:Humans; D051379:Mice; D011401:Promoter Regions, Genetic / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic
chemical_list: D001054:Apolipoproteins A; D017362:Cyclic AMP Response Element-Binding Protein; D012333:RNA, Messenger; C022205:apolipoprotein A-IV
keywords: ER stress; cAMP responsive element-binding protein H; hepatic steatosis