title: Binding of polyunsaturated fatty acids to LXRα and modulation of SREBP-1 interaction with a specific SCD1 promoter element.
abstract: Stearoyl-CoA desaturase 1 (SCD1) is the rate limiting enzyme in unsaturated fatty acid biosynthesis. This enzyme has an important role in the regulation of hepatic lipogenesis and lipid oxidation, and alterations in these pathways may lead to several diseases. We examined, in HepG2 cell cultures, the mechanism of SCD1 regulation considering the involvement of two transcription factors: liver X receptor alpha (LXRα) and sterol regulatory element-binding protein-1 (SREBP-1), also investigating the effect of dietary polyunsaturated fatty acids (PUFAs) on this process. The analysis of SCD1 promoter allowed to identify a functional SREBP-1 binding site (SRE 1). LXRα activation increased SCD1 protein level through upregulation of SREBP-1 and its consequent binding to SRE 1 sequence. Polyunsaturated docosahexaenoic acid (DHA, C22:6), eicosapentaenoic acid (EPA, C20:5) and arachidonic acid (AA, C20:4) were able to reduce SREBP-1 binding to SCD1 promoter, while saturated stearic acid (SA, C18:0) did not give any effect. Surface plasmon resonance analysis showed a direct binding of DHA, EPA and AA to LXRα. These data indicate a direct inhibitory interaction of PUFAs with LXRα, a consequent reduction of SREBP-1 and of its binding to SCD1 promoter. This information provides a mechanism to explain the regulation of lipogenic pathways induced by PUFAs.
authors.affiliation: Department of Pharmacy, University of Salerno, Fisciano, Salerno, Italy.
authors.forename: Mariella
authors.initials: M
authors.lastname: Caputo
authors.forename: Maria Caterina
authors.initials: MC
authors.lastname: De Rosa
authors.forename: Tania
authors.initials: T
authors.lastname: Rescigno
authors.forename: Hylde
authors.initials: H
authors.lastname: Zirpoli
authors.forename: Antonio
authors.initials: A
authors.lastname: Vassallo
authors.forename: Nunziatina
authors.initials: N
authors.lastname: De Tommasi
authors.forename: Gaetano
authors.initials: G
authors.lastname: Torino
authors.forename: Mario Felice
authors.initials: MF
authors.lastname: Tecce
mesh_terms: D005231:Fatty Acids, Unsaturated / Q000378:metabolism*; D056945:Hep G2 Cells; D006801:Humans; D000071518:Liver X Receptors; D057093:Orphan Nuclear Receptors / Q000378:metabolism*; D011485:Protein Binding; D020218:Response Elements; D013230:Stearoyl-CoA Desaturase / Q000235:genetics* / Q000378:metabolism; D051780:Sterol Regulatory Element Binding Protein 1 / Q000235:genetics / Q000378:metabolism*
chemical_list: D005231:Fatty Acids, Unsaturated; D000071518:Liver X Receptors; C000605213:NR1H3 protein, human; D057093:Orphan Nuclear Receptors; C497387:SREBF1 protein, human; D051780:Sterol Regulatory Element Binding Protein 1; C523776:SCD1 protein, human; D013230:Stearoyl-CoA Desaturase
keywords: arachidonic acid; docosahexaenoic acid; eicosapentaenoic acid; gene expression; lipogenic pathways; surface plasmon resonance