Polyunsaturated fatty acids inhibit S14 gene transcription in rat liver and cultured hepatocytes.

Abstract

Polyunsaturated fatty acids (PUFAs) have been shown to have significant effects on hepatic lipogenic gene expression. The S14 gene has been used as a model to examine the effects of PUFAs on hepatic lipogenic gene expression. In vivo studies showed that feeding rats a high carbohydrate diet containing menhaden oil rapidly (within hours) and signfficantly (250%) attenuates hepatic S14 gene transcription and S14 mRNA abundance. The suppressive effect of menhaden oil was both gene and tissue specific. The effect of PUFAs on expression of the S14 mRNA and a transected S14 fusion gene (i.e., S14CAT4.3) was examined in cultured hepatocytes in the presence of trilodothyronine (T3), insulin, dexamethasone, and albumin under serum-free conditions. Whereas T3 stimulated both S14 mRNA (>40-fold) and S14CAT4.3 (>100-fold), eicosapentaenoic acid (C20:5a3) significantly attenuated (>80%) both S14 mRNA and S14CAT activity in a dosedependent fashion. The effects of C20:5 on hepatocyte gene expression were both gene and fatty acid specflc. Deletion analysis of transfected S14CAT fusion genes indicated that the S14 thyroid hormone response element (at -2.5 to -2.9 kb) was not sensitive to C20:5 control. The cis-linked PUFA response elements were localized to a region within the S14 proxinal promoter (at -80 to -220 bp). This region also contains cis-acting elements that potentiate T3 actVation of S14 gene ranscription. These studies suggest that C20:5 (or its metabolites) regulates factors within the S14 proximal promoter region that are important for T3 activation of S14 gene tanscription.Dietary polyunsaturated fatty acids (PUFAs), particularly those rich in 20-and 22-carbon (w3 and w6) fatty acids, have several unique metabolic effects including suppression of very low density lipoprotein production, reduction of cholesterol synthesis, diminution of blood pressure, and modulation of the growth of certain carcinomas (1-3). A particularly intriguing feature of PUFAs is their ability to regulate the expression of several genes involved in lipid metabolism, such as the genes encoding apolipoprotein AI (4), low density lipoprotein receptors (5), glucose-6-phosphate dehydrogenase (6), and fatty acid synthase and the S14 protein (7)(8)(9).PUFAs suppress the hepatic mRNAs coding for the S14 protein (pI 4.9; 17 kDa) in both adult and weaning rats by inhibiting S14 gene transcription (7-9). S14 gene transcription is induced by 3,5,3'-triiodothyronine (T3) (10,11) Rats (one rat per cage) were meal-fed a high carbohydrate (Hi-CHO; 58% glucose; ICN, Cleveland, OH)/fat-free diet from 9 a.m. until 12 noon daily (9). Diets were supplemented (at 10% wt/wt) with either triolein [1,2,3-tri(cis-9-octadecenoyl)-glycerol; >95%; Sigma] or menhaden oil (MaxEPA, Scherer, FL). All diets contained butylated hydroxytoluene at 0.1% wt/wt (9,21). Gas chromatographic analysis showed that menhaden oil contained 433.5 mg ofpolyenes perg as w03 fatty acids (347.1 mg/g) and w6 fatty acids (26.6 mg/g). EPA and DHA were present at 160.9 mg/g and 112.4...

The Role of Liver X Receptor-α in the Fatty Acid Regulation of Hepatic Gene Expression

“…Previous studies established that the PUFA-RR, binding both SREBP-1c and NF-Y, is indispensable for S14 gene transcription. Moreover, this region is the principal target for PUFA control of the S14 promoter activity (28,32,33). These findings indicate that the key elements involved in PUFA control of S14 are distinct from the GlRR containing T1317-regulated factors.…”

“…Mutation of either element essentially abrogates S14 gene transcription (28,32). The SRE/nuclear factor-y elements are in the S14 PUFA-RR, a region previously identified as the principal target for PUFA suppression of S14 gene transcription (33). The FAS promoter has distinct regulatory elements for both SREBP and LXR (3).…”

Stimulatory effect of unsaturated fatty acids on the level of plasminogen activator inhibitor‐1 mRNA in cultured human endothelial cells

“…5). We could also localize these consensus sequences in the promoter region of the murine PAI-1 gene, as well as in the regulatory regions of the rat S14 and murine aP2 genes, both of which have been reported to be transcriptionally regulated by fatty acids [23,25] (Fig. 5).…”

“…One potential explanation could be that the fatty acids are directly involved in transcriptional regulation of the PAI-1 gene. An interesting feature of the polyunsaturated fatty acids is their ability to regulate the expression of genes by binding to fatty acid responsive factors [22,23,25]. Sloots et al identified consensus nucleotide sequences in the upstream region of five oleic acid-inducible genes of the diploid yeast Candida lropicalis.…”

“…Exogenously provided fatty acid can serve as a biological effector [18]. Fatty acids can also be directly involved in regulating gene expression by binding to specific, fatty acidresponsive transcription factors [19][20][21][22][23][24][25].…”