TitleSterol response element-binding protein 1c (SREBP1c) is involved in the polyunsaturated fatty acid suppression of hepatic S14 gene transcription.
Publication TypeJournal Article
Year of Publication1999
AuthorsMater, MK, Thelen, AP, Pan, DA, Jump, DB
JournalJ Biol Chem
Volume274
Issue46
Pagination32725-32
Date Published1999 Nov 12
ISSN0021-9258
KeywordsAnimals, CCAAT-Enhancer-Binding Proteins, Cells, Cultured, DNA-Binding Proteins, fas Receptor, Fatty Acid Synthases, Fatty Acids, Unsaturated, Gene Expression Regulation, Genes, Reporter, Liver, Male, Nuclear Proteins, Promoter Regions, Genetic, Proteins, Pyruvate Kinase, Rats, Receptors, Cytoplasmic and Nuclear, RNA, Messenger, Sterol Regulatory Element Binding Protein 1, Suppression, Genetic, Transcription Factors, Transfection, Triglycerides
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.

Alternate JournalJ. Biol. Chem.
PubMed ID10551830
Grant ListR01 DK043220 / DK / NIDDK NIH HHS / United States
DK 43220 / DK / NIDDK NIH HHS / United States