Effect of polyunsaturated fatty acids on lipogenic factors.

Polyunsaturated fatty acids (PUFA) are nutrients with relevant biological activities and preventive effects of cardiovascular and neoplastic diseases and therefore it is important to characterize the molecular processes involved in their action. On this purpose, we evaluated the effect of PUFA on Stearoyl-CoA Desaturase 1 (SCD1), the rate limiting enzyme in PUFA biosynthesis and on Sterol Regulatory Element Binding Protein (SREBP-1c), a transcription factor which directly modulate its expression. SCD1, introducing a double bond in fatty acyl-CoA substrates, is of particular interest since alterations of its activity seem to be involved in several dyslipidemic conditions. Considering that Liver X Receptor (LXR) activation induces lipogenic pathways also trough SREBP-1c regulation, we analyzed the effect of a specific LXR agonist molecule, T0901317, on a human hepatoma cell line (HepG2). Our data show a significant induction of SREBP-1c and SCD1 by T0901317. In addition, we analyzed some putative transcription factor binding sites within SCD1 gene promoter sequence. Using chromatin immunoprecipitation (ChIP) assay, we identified a functional binding site (-789/-659 SRE1 region). Data show an increased SREBP-1c binding after LXR activation. We analyzed the effects of individual PUFA on this mechanism. Results show that docosahexaenoic acid (DHA, C22:6), eicosapentaenoic acid (EPA, C20:5) and arachidonic acid (AA, C20:4) are able to reduce SREBP-1c binding on SRE1 region, while a saturated stearic acid (SA) did not give any effect. To further understand if PUFA produce these effects through a direct interaction with LXR, we have also carried out a surface plasmon resonance (SPR) analysis which showed a direct binding of DHA, EPA and AA on LXR transcription factor, while no interaction was found with saturated SA, indicating that these effects are specific. We conclude that analyzed PUFA selectively down-regulate lipogenic pathways through LXR inhibition and consequent SREBP-1c and SCD1 expression down-regulation