Sterol Regulatory Element Binding Protein-1 Expression Is Suppressed by Dietary Polyunsaturated Fatty Acids

Abstract

Polyunsaturated fatty acids (PUFA) coordinately suppress the transcription of a wide array of hepatic lipogenic genes including fatty acid synthase (FAS) and acetyl-CoA carboxylase. Interestingly, the over-expression of sterol regulatory element binding protein-1 (SREBP-1) induces the expression of all of the enzymes suppressed by PUFA. This observation led us to hypothesize that PUFA coordinately inhibit lipogenic gene transcription by suppressing the expression of SREBP-1. Our initial studies revealed that the SREBP-1 and FAS mRNA contents of HepG2 cells were reduced by 20:4(n-6) in a dose-dependent manner (i.e. EC 50 ϳ10 M), whereas 18:1(n-9) had no effect. Similarly, supplementing a fat-free, high glucose diet with oils rich in (n-6) or (n-3) PUFA reduced the hepatic content of precursor and nuclear SREBP-1 60 and 85%, respectively; however, PUFA had no effect on the nuclear content of upstream stimulatory factor (USF)-1. The PUFA-dependent decrease in nuclear content of mature SREBP-1 was paralleled by a 70 -90% suppression in FAS gene transcription. In contrast, dietary 18:1(n-9), i.e. triolein, had no inhibitory influence on the expression of SREBP-1 or FAS. The decrease in hepatic expression of SREBP-1 and FAS associated with PUFA ingestion was mimicked by supplementing the fat-free diet with the PPAR␣-activator, WY 14,643. Interestingly, nuclear run-on assays revealed that changes in SREBP-1 mRNA abundance were not accompanied by changes in SREBP-1 gene transcription. These results support the concept that PUFA coordinately inhibit lipogenic gene transcription by suppressing the expression of SREBP-1 and that the PUFA regulation of SREBP-1 appears to occur at the post-transcriptional level.Dietary polyunsaturated fatty acids (PUFA) 1 are effective hypolipidemic agents (1), and they exert this effect by coordinately suppressing hepatic lipid synthesis and secretion while inducing hepatic and skeletal muscle fatty acid oxidation (2-10). Dietary PUFA coordinately decrease the transcription of hepatic genes encoding glycolytic and lipogenic enzymes (fatty acid synthase, acetyl-CoA carboxylase, stearoyl-CoA desaturase, malic enzyme, L-pyruvate kinase, and glucokinase) (3, 11-15), whereas they concomitantly increase the transcription of genes encoding enzymes involved in fatty acid oxidation (carnitine palmitoyltransferase (16) and acyl-CoA oxidase (9)). The outcome is a decrease in hepatic lipogenesis and an increase in hepatic fatty acid oxidation and ketogenesis. Genes encoding the oxidative enzymes appear to be regulated by a common transcription factor, peroxisomal proliferator-activated receptor (PPAR) (9, 16 -21). Because PPARs are lipidactivated transcription factors, they have often been proposed as the "master switches" that regulate the expression of enzymes involved in lipid synthesis and degradation (19 -21). However, several lines of evidence, including studies with PPAR␣ knock-out mice, indicate that the PUFA suppression of lipogenic gene transcription does not directly involve PPAR␣ (22,23).De...

Effects of dietary lipids and Clostridium butyricum on serum lipids and lipid-related gene expression in broiler chickens

“…This contradicts previous studies demonstrating that polyunsaturated fatty acids (PUFA) inhibited lipogenic gene transcription by suppressing SREBP-1c expression (Kim et al, 1999;Xu et al, 1999). Xu et al (1999) also indicated that the SREBP-1 mRNA content of cells was reduced by 20:4n-6 fatty acids in a dose-dependent manner, whereas 18:1n-9 had no effect. However, the exact amount of 20:4n-6 fatty acids was not determined by Yang et al (2010).…”

Dietary fat modifies lipid metabolism in the adipose tissue of metabolic syndrome patients

“…This idea is supported by the fact that the overexpression of mature SREBP1 overrides the PUFA suppression of lipogenic gene expression (Yahagi et al 1999), and by a study using animal models which showed that the decrease of the mature form of SREBP1 after administration of fish oil rich in n-3 PUFA results in decreased expression of lipogenic enzymes including SCD1 (Xu et al 1999). Moreover, n-3 PUFA has been related to the control of the proteolytic processing of SREBP precursors (Pegorier et al 2004) and its modulator effect in decreasing the lipogenesis process through inhibition of SREBP1 in adipocytes (Madsen et al 2005).…”

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