title: Human SREBP1c expression in liver is directly regulated by peroxisome proliferator-activated receptor alpha (PPARalpha).
abstract: Sterol regulatory element binding proteins (SREBPs) regulate the expression of a number of enzymes, which catalyze the synthesis of fatty acids, cholesterol, triglycerides, and phospholipids. SREBP1c is the most relevant isoform in the adult liver, and its expression is controlled by the nutritional state. Transcriptional regulation studies into the SREBP1c gene, performed in the last few years, have improved our knowledge of the variability of signals that converge on its promoter region. Insulin, cholesterol derivatives, T3 and other endogenous molecules have been demonstrated to regulate the SREBP1c expression, particularly in rodents. The present study aimed to perform a detailed analysis of the human SREBP1c gene promoter structure in liver cells by focusing on responses to diverse metabolic signals. Serial deletion and mutation assays reveal that both SREBP (SRE) and LXR (LXRE) response elements are involved in SREBP1c transcription regulation mediated by insulin and cholesterol derivatives. We discovered that peroxisome proliferation-activated receptor alpha (PPARα) agonists enhance the activity of the SREBP1c promoter; a DR1 element, at -453 in the human promoter was involved in this activation. Moreover, PPARα agonists act in cooperation with LXR or insulin to induce lipogenesis. Collectively, our results identify PPARα as a novel regulatory factor in SREBP1c regulation which plays a relevant role in the interplay between lipids and insulin metabolic regulation.
authors.affiliation: Instituto de Biomedicina de Valencia, IBV-CSIC, Jaime Roig 11, 46010 Valencia, Spain.
authors.forename: Ana
authors.initials: A
authors.lastname: Fernández-Alvarez
authors.forename: María Soledad
authors.initials: MS
authors.lastname: Alvarez
authors.forename: Raúl
authors.initials: R
authors.lastname: Gonzalez
authors.forename: Carme
authors.initials: C
authors.lastname: Cucarella
authors.forename: Jordi
authors.initials: J
authors.lastname: Muntané
authors.forename: Marta
authors.initials: M
authors.lastname: Casado
mesh_terms: D000818:Animals; D001483:Base Sequence; D002784:Cholesterol / Q000378:metabolism; D004252:DNA Mutational Analysis; D022781:Hepatocytes / Q000378:metabolism; D006801:Humans; D007328:Insulin / Q000378:metabolism; D051379:Mice; D008969:Molecular Sequence Data; D009154:Mutation; D047493:PPAR alpha / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D051381:Rats; D012689:Sequence Homology, Nucleic Acid; D051780:Sterol Regulatory Element Binding Protein 1 / Q000096:biosynthesis* / Q000235:genetics
chemical_list: D007328:Insulin; D047493:PPAR alpha; D051780:Sterol Regulatory Element Binding Protein 1; D002784:Cholesterol