N-3 polyunsaturated fatty acids suppress insulin-induced SREBP-1c transcription via reduced trans-activating capacity of LXRalpha.
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 LXRalpha 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 LXRalpha-dependent activation of both the wild type SREBP-1c promoter and the synthetic LXRE-driven promoter, and significantly blunted LXRalpha-dependent activation of a Gal4-LXRalpha chimeric protein thus demonstrating that n-3 PUFA effectively mitigate induction of SREBP-1c by insulin via reduced trans-activation of LXRalpha.
Howell
George
G
Department of Pharmacology, University of Tennessee Health Sciences Center, Memphis, TN 38163, USA.
Deng
Xiong
X
Yellaturu
Chandrahassa
C
Park
Edwards A
EA
Wilcox
Henry G
HG
Raghow
Rajendra
R
Elam
Marshall B
MB
D000818:Animals; D001665:Binding Sites; D015525:Fatty Acids, Omega-3 / Q000494:pharmacology*; D007328:Insulin / Q000494:pharmacology*; D050155:Lipogenesis / Q000235:genetics; D000071518:Liver X Receptors; D008156:Luciferases / Q000378:metabolism; D009154:Mutation / Q000235:genetics; D057093:Orphan Nuclear Receptors / Q000819:agonists / Q000037:antagonists & inhibitors / Q000235:genetics*; D051381:Rats; D020218:Response Elements / Q000235:genetics; D051780:Sterol Regulatory Element Binding Protein 1 / Q000235:genetics*; D014158:Transcription, Genetic / Q000187:drug effects*; D015533:Transcriptional Activation / Q000187:drug effects*
D015525:Fatty Acids, Omega-3; D007328:Insulin; D000071518:Liver X Receptors; C000605215:Nr1h3 protein, rat; D057093:Orphan Nuclear Receptors; D051780:Sterol Regulatory Element Binding Protein 1; D008156:Luciferases