N-3 polyunsaturated fatty acids suppress insulin-induced SREBP-1c transcription via reduced trans-activating capacity of LXRα

George Howell, Xiong Deng, Chandrahassa Yellaturu, Edwards Park, Henry G. Wilcox, Rajendra Raghow, Marshall Elam

Research output: Contribution to journalArticle

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Abstract

Insulin coordinately up-regulates lipogenic gene transcription via induction of sterol regulatory element binding protein-1c (SREBP-1c). Conversely, polyunsaturated fatty acids (PUFA) decrease lipogenic gene transcription via suppression of SREBP-1c. We therefore examined the ability of n-3 PUFA to mitigate induction of SREBP-1c and its downstream lipogenic targets by insulin in primary rat hepatocyte cultures. Insulin induced expression of SREBP-1c mRNA 5-6 fold as well as rat SREBP-1c promoter activity. These effects were prevented by the n-3 fatty acids eicosapentaenoic acid (20:5 n-3; EPA) and docosahexaenoic acid (22:6 n-3, DHA), but not by the monounsaturated fatty acid oleic acid (18:1 n-6, OLA). N-3 fatty acids also effectively prevented insulin induction of the downstream lipogenic enzyme targets fatty acid synthase (FAS) and acetyl carboxyl coenzyme acetyltransferase-1 (ACC-1), and reduced de novo lipogenesis. The SREBP-1c promoter contains an insulin response unit consisting of tandem LXRα response elements (LXREs) as well as sites for NF-Y, Sp1, and SREBP-1c itself. The LXREs were identified as a primary site mediating suppression of SREBP-1c transcription by n-3 PUFA. DHA effectively prevented LXRα-dependent activation of both the wild type SREBP-1c promoter and the synthetic LXRE-driven promoter, and significantly blunted LXRα-dependent activation of a Gal4-LXRα chimeric protein thus demonstrating that n-3 PUFA effectively mitigate induction of SREBP-1c by insulin via reduced trans-activation of LXRα.

Original languageEnglish (US)
Pages (from-to)1190-1196
Number of pages7
JournalBiochimica et Biophysica Acta - Molecular and Cell Biology of Lipids
Volume1791
Issue number12
DOIs
StatePublished - Sep 17 2009

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Sterol Regulatory Element Binding Protein 1
Omega-3 Fatty Acids
Insulin
Response Elements
Fatty Acid Synthases
Monounsaturated Fatty Acids
Lipogenesis
Acetyltransferases
Eicosapentaenoic Acid
Docosahexaenoic Acids
Coenzymes
Oleic Acid
Unsaturated Fatty Acids
Genes
Hepatocytes
Up-Regulation

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Cell Biology

Cite this

N-3 polyunsaturated fatty acids suppress insulin-induced SREBP-1c transcription via reduced trans-activating capacity of LXRα. / Howell, George; Deng, Xiong; Yellaturu, Chandrahassa; Park, Edwards; Wilcox, Henry G.; Raghow, Rajendra; Elam, Marshall.

In: Biochimica et Biophysica Acta - Molecular and Cell Biology of Lipids, Vol. 1791, No. 12, 17.09.2009, p. 1190-1196.

Research output: Contribution to journalArticle

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