title: Suppression of the pancreatic duodenal homeodomain transcription factor-1 (Pdx-1) promoter by sterol regulatory element-binding protein-1c (SREBP-1c).
abstract: Overexpression of sterol regulatory element-binding protein-1c (SREBP-1c) in β cells causes impaired insulin secretion and β cell dysfunction associated with diminished pancreatic duodenal homeodomain transcription factor-1 (PDX-1) expression in vitro and in vivo. To identify the molecular mechanism responsible for this effect, the mouse Pdx-1 gene promoter (2.7 kb) was analyzed in β cell and non-β cell lines. Despite no apparent sterol regulatory element-binding protein-binding sites, the Pdx-1 promoter was suppressed by SREBP-1c in β cells in a dose-dependent manner. PDX-1 activated its own promoter. The E-box (-104/-99 bp) in the proximal region, occupied by ubiquitously expressed upstream stimulatory factors (USFs), was crucial for the PDX-1-positive autoregulatory loop through direct PDX-1·USF binding. This positive feedback activation was a prerequisite for SREBP-1c suppression of the promoter in non-β cells. SREBP-1c and PDX-1 directly interact through basic helix-loop-helix and homeobox domains, respectively. This robust SREBP-1c·PDX-1 complex interferes with PDX-1·USF formation and inhibits the recruitment of PDX-1 coactivators. SREBP-1c also inhibits PDX-1 binding to the previously described PDX-1-binding site (-2721/-2646 bp) in the distal enhancer region of the Pdx-1 promoter. Endogenous up-regulation of SREBP-1c in INS-1 cells through the activation of liver X receptor and retinoid X receptor by 9-cis-retinoic acid and 22-hydroxycholesterol inhibited PDX-1 mRNA and protein expression. Conversely, SREBP-1c RNAi restored Pdx-1 mRNA and protein levels. Through these multiple mechanisms, SREBP-1c, when induced in a lipotoxic state, repressed PDX-1 expression contributing to the inhibition of insulin expression and β cell dysfunction.
authors.affiliation: Okinaka Memorial Institute for Medical Research, Toranomon Hospital, Tokyo 105-8470, Japan. michiyoame-tky@umin.ac.jp
authors.forename: Michiyo
authors.initials: M
authors.lastname: Amemiya-Kudo
authors.forename: Junko
authors.initials: J
authors.lastname: Oka
authors.forename: Yoshinori
authors.initials: Y
authors.lastname: Takeuchi
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Okazaki
authors.forename: Takashi
authors.initials: T
authors.lastname: Yamamoto
authors.forename: Naoya
authors.initials: N
authors.lastname: Yahagi
authors.forename: Kaori
authors.initials: K
authors.lastname: Matsuzaka
authors.forename: Sachiko
authors.initials: S
authors.lastname: Okazaki
authors.forename: Jun-ichi
authors.initials: J
authors.lastname: Osuga
authors.forename: Nobuhiro
authors.initials: N
authors.lastname: Yamada
authors.forename: Toshio
authors.initials: T
authors.lastname: Murase
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Shimano
mesh_terms: D000077556:Alitretinoin; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D056945:Hep G2 Cells; D018398:Homeodomain Proteins / Q000096:biosynthesis* / Q000235:genetics; D006801:Humans; D007328:Insulin / Q000096:biosynthesis* / Q000235:genetics; D050417:Insulin-Secreting Cells / Q000378:metabolism*; D000071518:Liver X Receptors; D051379:Mice; D057093:Orphan Nuclear Receptors / Q000235:genetics / Q000378:metabolism; D020218:Response Elements / Q000502:physiology*; D051780:Sterol Regulatory Element Binding Protein 1 / Q000235:genetics / Q000378:metabolism*; D015534:Trans-Activators / Q000096:biosynthesis* / Q000235:genetics; D014212:Tretinoin / Q000494:pharmacology; D015854:Up-Regulation / Q000187:drug effects / Q000502:physiology*; D051720:Upstream Stimulatory Factors / Q000235:genetics / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D018398:Homeodomain Proteins; D007328:Insulin; D000071518:Liver X Receptors; D057093:Orphan Nuclear Receptors; D051780:Sterol Regulatory Element Binding Protein 1; D015534:Trans-Activators; D051720:Upstream Stimulatory Factors; C084010:pancreatic and duodenal homeobox 1 protein; D000077556:Alitretinoin; D014212:Tretinoin