title: Effects of fish oil feeding and fasting on LXRalpha/RXRalpha binding to LXRE in the SREBP-1c promoter in mouse liver.
abstract: High-fish oil feeding and fasting down-regulate sterol regulatory element-binding protein-1c (SREBP-1c) mRNA level and suppress lipogenesis in mouse liver. Previous promoter analysis revealed that liver X receptor alpha (LXRalpha)/retinoid X receptor alpha (RXRalpha) complex was required for SREBP-1c gene expression in cell culture. In in vitro studies, polyunsaturated fatty acids (PUFAs, n-6, n-3) inhibited binding of LXRalpha/RXRalpha heterodimer to LXR responsive elements (LXREs) in the SREBP-1c promoter. To examine whether fish oil feeding and fasting would also inhibit its binding to LXREs in mouse liver, active liver nuclear extracts were prepared by percoll gradient centrifugation, and gel mobility shift assay was conducted. Although 1- to 5-day fish oil feeding and 2-day fasting decreased SREBP-1c mRNA by 45-68% and 65%, respectively, fish oil feeding decreased binding of LXR/RXR heterodimer to LXREs by 0-26%, while 2-day fasting decreased their binding by 40-56%. Luciferase assay using mutation of LXREs in mouse primary hepatocytes revealed that the LXR ligand, T0901317, induced increased transcription of SREBP-1c mRNA was mediated by LXREs, but it is unknown whether fish oil/eicosapentaenoic acid (EPA)-induced down-regulation of SREBP-1c mRNA was mediated by LXREs. These data indicate that high-fish oil feeding might decrease SREBP-1c mRNA partly by decreased transcription of SREBP-1c, but if so, the binding inhibition of LXRalpha to LXREs might not be a major cause, while fasting decreased SREBP-1c mRNA, mainly by its binding inhibition of LXRalpha to LXREs in the SREBP-1c promoter.
authors.affiliation: Division of Clinical Nutrition, National Institute of Health and Nutrition, 1-23-1, Toyama, Tokyo 162-8636, Japan.
authors.forename: Teruyo
authors.initials: T
authors.lastname: Nakatani
authors.forename: Aki
authors.initials: A
authors.lastname: Katsumata
authors.forename: Shinji
authors.initials: S
authors.lastname: Miura
authors.forename: Yasutomi
authors.initials: Y
authors.lastname: Kamei
authors.forename: Osamu
authors.initials: O
authors.lastname: Ezaki
mesh_terms: D000818:Animals; D022762:CCAAT-Enhancer-Binding Proteins / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism*; D004042:Dietary Fats, Unsaturated / Q000378:metabolism; D004435:Eating; D024202:Electrophoretic Mobility Shift Assay; D005215:Fasting / Q000378:metabolism*; D005260:Female; D005395:Fish Oils / Q000008:administration & dosage*; D008099:Liver / Q000378:metabolism*; D000071518:Liver X Receptors; D051379:Mice; D008810:Mice, Inbred C57BL; D057093:Orphan Nuclear Receptors; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism*; D020218:Response Elements; D047490:Retinoid X Receptor alpha / Q000378:metabolism*; D051780:Sterol Regulatory Element Binding Protein 1; D014157:Transcription Factors / Q000235:genetics*
chemical_list: D022762:CCAAT-Enhancer-Binding Proteins; D004268:DNA-Binding Proteins; D004042:Dietary Fats, Unsaturated; D005395:Fish Oils; D000071518:Liver X Receptors; C000605214:Nr1h3 protein, mouse; D057093:Orphan Nuclear Receptors; D018160:Receptors, Cytoplasmic and Nuclear; D047490:Retinoid X Receptor alpha; C497388:Srebf1 protein, mouse; D051780:Sterol Regulatory Element Binding Protein 1; D014157:Transcription Factors