Sterol Response Element-binding Protein 1c (SREBP1c) Is Involved in the Polyunsaturated Fatty Acid Suppression of Hepatic S14 Gene Transcription

Michelle K Mater,Annette P Thelen,David A Pan,Donald B Jump

doi:10.1074/jbc.274.46.32725

Michelle K Mater, Annette P Thelen + Show 2 more

Open Access

https://doi.org/10.1074/jbc.274.46.32725

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Abstract

Polyunsaturated fatty acids (PUFA) suppress hepatic lipogenic gene transcription through a peroxisome proliferator activated receptor alpha (PPARalpha)- and cyclooxygenase-independent mechanism. Recently, the sterol response element-binding protein 1 (SREBP1) was implicated in the nutrient control of lipogenic gene expression. In this report, we have assessed the role SREBP1 plays in the PUFA control of three hepatic genes, fatty acid synthase, L-pyruvate kinase (LPK), and the S14 protein (S14). PUFA suppressed both the hepatic mRNA(SREBP1) through a PPARalpha-independent mechanism as well as SREBP1c nuclear content (nSREBP1c, 65 kDa). Co-transfection of primary hepatocytes revealed a differential sensitivity of the fatty acid synthase, S14, and LPK promoters to nSREBP1c overexpression. Of the three promoters examined, LPK was the least sensitive to overexpressed nSREBP1c. Promoter deletion and gel shift analyses of the S14 promoter localized a functional SREBP1c cis-regulatory element to an E-box-like sequence ((-139)TCGCCTGAT(-131)) within the S14 PUFA response region. Although overexpression of nSREBP1c significantly reduced PUFA inhibition of S14CAT, overexpression of other factors that induced S14CAT activity, such as steroid receptor co-activator 1 or retinoid X receptor alpha, had no effect on S14CAT PUFA sensitivity. These results suggest that PUFA regulates hepatic nSREBP1c, a factor that functionally interacts with the S14 PUFA response region. PUFA regulation of nSREBP1c may account for the PUFA-mediated suppression of hepatic S14 gene transcription.

Highlights

IntroductionPolyunsaturated fatty acids (PUFA) (both n-3 and n-6) are potent inhibitors of hepatic de novo lipogenesis
Polyunsaturated fatty acids (PUFA)1 are potent inhibitors of hepatic de novo lipogenesis
PUFA Down-regulates Hepatic sterol response element binding protein-1 (SREBP1) Gene Expression in Vivo through a PPAR␣-independent Mechanism—In CV1, COS, and HepG2 cells, unsaturated fatty acids suppress the nuclear content of SREBP1a [5], a transcription factor involved in the regulation of several lipogenic genes (6 –13, 17–20, 25– 27)

Summary

Introduction

Polyunsaturated fatty acids (PUFA) (both n-3 and n-6) are potent inhibitors of hepatic de novo lipogenesis. PPAR␣ is a ligand-activated nuclear receptor that regulates the expression of mitochondrial, peroxisomal, and microsomal enzymes involved in fatty acid metabolism. Recent studies by Worgall et al [5] provide an important clue to another factor involved in PUFA regulation of gene expression. Their studies suggest that unsaturated fatty acids regulate the nuclear abundance of the sterol response element binding protein-1 (SREBP1). Studies in transgenic mice overexpressing different SREBP subtypes suggest that SREBP1 may play a major role in the control of lipogenic gene expression, whereas SREBP2 functions in the regulation of cholesterol synthesis [7,8,9,10]

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