Effect of polyunsaturated fatty acids on lipogenic factors
Résumé fourni par la source
Polyunsaturated fatty acids (PUFA) are nutrients with relevant biological activities \nand preventive effects of cardiovascular and neoplastic diseases and therefore it is \nimportant to characterize the molecular processes involved in their action. On this \npurpose, we evaluated the effect of PUFA on Stearoyl-CoA Desaturase 1 (SCD1), the \nrate limiting enzyme in PUFA biosynthesis and on Sterol Regulatory Element Binding \nProtein (SREBP-1c), a transcription factor which directly modulate its expression. \nSCD1, introducing a double bond in fatty acyl-CoA substrates, is of particular interest \nsince alterations of its activity seem to be involved in several dyslipidemic conditions. \nConsidering that Liver X Receptor (LXR) activation induces lipogenic pathways \nalso trough SREBP-1c regulation, we analyzed the effect of a specific LXR agonist \nmolecule, T0901317, on a human hepatoma cell line (HepG2). Our data show a \nsignificant induction of SREBP-1c and SCD1 by T0901317. In addition, we analyzed \nsome putative transcription factor binding sites within SCD1 gene promoter sequence. \nUsing chromatin immunoprecipitation (ChIP) assay, we identified a functional binding \nsite (-789/-659 SRE1 region). Data show an increased SREBP-1c binding after LXR \nactivation. We analyzed the effects of individual PUFA on this mechanism. Results \nshow that docosahexaenoic acid (DHA, C22:6), eicosapentaenoic acid (EPA, C20:5) \nand arachidonic acid (AA, C20:4) are able to reduce SREBP-1c binding on SRE1 \nregion, while a saturated stearic acid (SA) did not give any effect. To further understand \nif PUFA produce these effects through a direct interaction with LXR, we have also \ncarried out a surface plasmon resonance (SPR) analysis which showed a direct \nbinding of DHA, EPA and AA on LXR transcription factor, while no interaction was \nfound with saturated SA, indicating that these effects are specific. We conclude that \nanalyzed PUFA selectively down-regulate lipogenic pathways through LXR inhibition \nand consequent SREBP-1c and SCD1 expression down-regulation.
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