Polyunsaturated fatty acid suppression of fatty acid synthase (FASN): evidence for dietary modulation of NF-Y binding to the Fasn promoter by SREBP-1c

Abstract

Dietary PUFAs (polyunsaturated fatty acids) co-ordinately suppress transcription of a group of hepatic genes encoding glycolytic and lipogenic enzymes. Suppression of Fasn (fatty acid synthase) transcription involves two PUFA-responsive regions, but the majority of PUFA sensitivity maps to a region within the proximal promoter containing binding sites for NF-Y (nuclear factor-Y), Sp1 (stimulatory protein 1), SREBP (sterol-regulatory-elementbinding protein), and USF (upstream stimulatory factor). Promoter activation assays indicate that altered NF-Y is the key component in regulation of Fasn promoter activity by PUFA. Using electrophoretic mobility-shift assay and chromatin immunoprecipitation analysis, we demonstrate for the first time that PUFAs decrease in vivo binding of NF-Y and SREBP-1c to the proximal promoter of the hepatic Fasn gene and the promoters of three additional genes, spot 14, stearoyl-CoA desaturase and farnesyl diphosphate synthase that are also down-regulated by PUFA. The comparable 50% decrease in NF-Y and SREBP-1c binding to the promoters of the respective PUFA-sensitive genes occurred despite no change in nuclear NF-Y content and a 4-fold decrease in SREBP-1c. Together, these findings support a mechanism whereby PUFA reciprocally regulates the binding of NF-Y and SREBP-1c to a subset of genes which share similar contiguous arrangements of sterol regulatory elements and NF-Y response elements within their promoters. PUFA-dependent regulation of SREBP-1c and NF-Y binding to this unique configuration of response elements may represent a nutrient-sensitive motif through which PUFA selectively and co-ordinately targets subsets of hepatic genes involved in lipid metabolism.

n-3 Fatty acids and rosiglitazone improve insulin sensitivity through additive stimulatory effects on muscle glycogen synthesis in mice fed a high-fat diet

“…The former mechanism was not studied in our experiments; however, we did demonstrate the inhibition of hepatic VLDL-triacylglycerol production by either DHA/EPA or rosiglitazone, with the strongest effect being observed in the combination treatment. The decrease of hepatic triacylglycerol production by DHA/EPA may represent a functional outcome of the coordinated suppression of lipogenic genes by n-3 LC-PUFA [17]. In addition, stimulation of AMP-activated protein kinase by n-3 LC-PUFA, resulting in a metabolic switch from lipogenesis to lipid catabolism, may also be involved [49].…”

“…Besides acting directly as regulatory ligands, n-3 LC-PUFA also act through their active metabolites, eicosanoids and other lipid molecules [16]. The hypolipidaemic and anti-obesity effects of n-3 LC-PUFA probably depend on the in situ suppression of lipogenesis and increase of fatty acid oxidation in several tissues [10,14,17]. This metabolic switch might reduce accumulation of toxic fatty acidderivatives, while protecting insulin signalling in liver and muscle [11,12,18].…”

Distinct regulation of stearoyl-CoA desaturase 1 gene expression by cis and trans C18:1 fatty acids in human aortic smooth muscle cells

“…Thus, a regulation of scd1 gene expression by MUFA might be mediated through the modulation of LXR signalling. Moreover, the NF-Y transcription factor has also been reported for its essential role in either the activation by sterol depletion or the inhibition by PUFA of scd1 promoter activity (Tabor et al 1999;Teran-Garcia et al 2007). The NF-Y response element is found in scd1 promoter, and the C18:1 fatty acids might play their effect by a regulation of NF-Y binding to the promoter (Tabor et al 1999).…”

n-3 PUFA: bioavailability and modulation of adipose tissue function

“…However, PPARg, liver X receptor-a, hepatic nuclear factor-4, sterol regulatory element-binding protein-1 and NF-kB (7) are also involved (30)(31)(32) . The hypolipidaemic and anti-obesity effects of n-3 LC PUFA probably depend on the in situ suppression of lipogenesis and increase in fatty acid oxidation in several tissues including liver, intestine, and adipose tissue (12,31,33,34) . This metabolic switch may reduce the accumulation of toxic fatty acid derivatives, while protecting the insulin signalling in liver and muscle (9,13,24,30,35) .…”