title: SREBP-1c regulates glucose-stimulated hepatic clusterin expression.
abstract: Clusterin is a stress-response protein that is involved in diverse biological processes, including cell proliferation, apoptosis, tissue differentiation, inflammation, and lipid transport. Its expression is upregulated in a broad spectrum of diverse pathological states. Clusterin was recently reported to be associated with diabetes, metabolic syndrome, and their sequelae. However, the regulation of clusterin expression by metabolic signals was not addressed. In this study we evaluated the effects of glucose on hepatic clusterin expression. Interestingly, high glucose concentrations significantly increased clusterin expression in primary hepatocytes and hepatoma cell lines, but the conventional promoter region of the clusterin gene did not respond to glucose stimulation. In contrast, the first intronic region was transcriptionally activated by high glucose concentrations. We then defined a glucose response element (GlRE) of the clusterin gene, showing that it consists of two E-box motifs separated by five nucleotides and resembles carbohydrate response element (ChoRE). Unexpectedly, however, these E-box motifs were not activated by ChoRE binding protein (ChREBP), but were activated by sterol regulatory element binding protein-1c (SREBP-1c). Furthermore, we found that glucose induced recruitment of SREBP-1c to the E-box of the clusterin gene intronic region. Taken together, these results suggest that clusterin expression is increased by glucose stimulation, and SREBP-1c plays a crucial role in the metabolic regulation of clusterin.
authors.affiliation: Department of Pharmacology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea.
authors.forename: Gukhan
authors.initials: G
authors.lastname: Kim
authors.forename: Geun Hyang
authors.initials: GH
authors.lastname: Kim
authors.forename: Gyun-Sik
authors.initials: GS
authors.lastname: Oh
authors.forename: Jin
authors.initials: J
authors.lastname: Yoon
authors.forename: Hae Won
authors.initials: HW
authors.lastname: Kim
authors.forename: Min-Seon
authors.initials: MS
authors.lastname: Kim
authors.forename: Seung-Whan
authors.initials: SW
authors.lastname: Kim
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D047369:Chromatin Immunoprecipitation; D051152:Clusterin / Q000235:genetics*; D005947:Glucose / Q000378:metabolism* / Q000494:pharmacology; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism*; D051379:Mice; D020218:Response Elements; D051780:Sterol Regulatory Element Binding Protein 1 / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic / Q000187:drug effects; D015533:Transcriptional Activation
chemical_list: D051152:Clusterin; C497388:Srebf1 protein, mouse; D051780:Sterol Regulatory Element Binding Protein 1; D005947:Glucose