Dietary cholesterol opposes PUFA-mediated repression of the stearoyl-CoA desaturase-1 gene by SREBP-1 independent mechanism.
Stearoyl-CoA desaturase (SCD) catalyzes the rate-limiting step in the cellular synthesis of monounsaturated fatty acids, mainly oleate (18:1) and palmitoleate (16:1), which are the major monounsaturated fatty acids of membrane phospholipids, cholesteryl esters, waxes, and triglycerides. The mouse expresses three well-characterized SCD genes (SCD1, 2, and 3). SCD1 is the main isoform expressed in the liver of mice. Previous in vivo studies have shown that the transcriptional repression by n-3 and n-6 polyunsaturated fatty acids (PUFAs) and the induction by cholesterol of the SCD1 gene are dependent on the maturation of the sterol regulatory element-binding protein-1c (SREBP-1c). We studied the regulation of SREBP-1, SCD1, and other SREBP-1 target genes when a high cholesterol diet is combined with PUFA as n-6 PUFA rich soybean oil (SO), or n-3 PUFA rich fish oil (FO). While the PUFA/cholesterol (PUFA/CH) diets repressed the maturation of the SREBP-1, the SCD1 mRNA levels, and protein and enzyme activity were induced. Compared with PUFA diets, hepatic cholesterol ester and triglyceride were enriched with 16:1 and 18:1 monounsaturated fatty acids in mice fed PUFA/CH diets. Total plasma cholesterol levels were not altered but plasma triglycerides were reduced in SO/CH-fed mice compared with SO-fed mice. The mRNA for SREBP-1 was increased by the PUFA/CH diet but the mRNA levels of SREBP-1 target genes such as fatty acid synthase and LDL receptor were decreased, indicating that the main control of PUFA-mediated suppression of SREBP-1 target genes is the maturation of SREBP-1. This study demonstrates that cholesterol overrides the PUFA-mediated repression of the SCD1 gene and regulates SCD1 gene expression through a mechanism independent of SREBP-1 maturation.
D000818:Animals; D015152:Blotting, Northern; D022762:CCAAT-Enhancer-Binding Proteins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D002784:Cholesterol / Q000032:analysis; D002791:Cholesterol, Dietary / Q000494:pharmacology*; D004268:DNA-Binding Proteins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology; D005231:Fatty Acids, Unsaturated / Q000494:pharmacology*; D005260:Female; D020868:Gene Silencing / Q000187:drug effects*; D015151:Immunoblotting; D008055:Lipids / Q000032:analysis / Q000737:chemistry; D008099:Liver / Q000737:chemistry / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D013230:Stearoyl-CoA Desaturase / Q000096:biosynthesis / Q000235:genetics* / Q000378:metabolism; D051780:Sterol Regulatory Element Binding Protein 1; D014157:Transcription Factors; D014158:Transcription, Genetic
D022762:CCAAT-Enhancer-Binding Proteins; D002791:Cholesterol, Dietary; D004268:DNA-Binding Proteins; D005231:Fatty Acids, Unsaturated; D008055:Lipids; C497388:Srebf1 protein, mouse; D051780:Sterol Regulatory Element Binding Protein 1; D014157:Transcription Factors; D002784:Cholesterol; D013230:Stearoyl-CoA Desaturase