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Nur77 modulates hepatic lipid metabolism through suppression of SREBP1c activity

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Author: Pols, T.W.H. · Ottenhoff, R. · Vos, M. · Levels, J.H.M. · Quax, P.H.A. · Meijers, J.C.M. · Pannekoek, H. · Groen, A.K. · Vries, C.J.M. de
Type:article
Date:2008
Institution: TNO Kwaliteit van Leven
Source:Biochemical and Biophysical Research Communications, 4, 366, 910-916
Identifier: 240659
doi: doi:10.1016/j.bbrc.2007.12.039
Keywords: Biology · Lipid metabolism · NR4A nuclear receptors · NR4A1 · Nur77 · SREBP1c · Sterol regulatory element binding protein-1 · ABC transporter · ABC transporter G5 · ABC transporter G8 · acyl coenzyme A desaturase · acyl coenzyme A desaturase 1 · adenovirus vector · fatty acid synthase · glycerol 3 phosphate acyltransferase · low density lipoprotein receptor · nuclear receptor Nur77 · sterol regulatory element binding protein 1c · triacylglycerol · animal experiment · animal tissue · article · controlled study · enzyme activity · enzyme repression · gene expression · genetic analysis · lipid blood level · lipid liver level · lipid metabolism · male · mouse · nonhuman · nucleotide sequence · priority journal · protein expression · protein function · Adenoviridae · Animals · DNA-Binding Proteins · Gene Expression Regulation · Lipid Metabolism · Liver · Male · Mice · Mice, Inbred C57BL · Receptors, Cytoplasmic and Nuclear · Receptors, Steroid · RNA, Messenger · Sterol Regulatory Element Binding Protein 1 · Transcription Factors · Triglycerides · Mus

Abstract

NR4A nuclear receptors are induced in the liver upon fasting and regulate hepatic gluconeogenesis. Here, we studied the role of nuclear receptor Nur77 (NR4A1) in hepatic lipid metabolism. We generated mice expressing hepatic Nur77 using adenoviral vectors, and demonstrate that these mice exhibit a modulation of the plasma lipid profile and a reduction in hepatic triglyceride. Expression analysis of >25 key genes involved in lipid metabolism revealed that Nur77 inhibits SREBP1c expression. This results in decreased SREBP1c activity as is illustrated by reduced expression of its target genes stearoyl-coA desaturase-1, mitochondrial glycerol-3-phosphate acyltransferase, fatty acid synthase and the LDL receptor, and provides a mechanism for the physiological changes observed in response to Nur77. Expression of LXR target genes Abcg5 and Abcg8 is reduced by Nur77, and may suggest involvement of LXR in the inhibitory action of Nur77 on SREBP1c expression. Taken together, our study demonstrates that Nur77 modulates hepatic lipid metabolism through suppression of SREBP1c activity. © 2007 Elsevier Inc. All rights reserved. Chemicals / CAS: acyl coenzyme A desaturase, 9014-34-0; fatty acid synthase, 9045-77-6; glycerol 3 phosphate acyltransferase, 9029-96-3; DNA-Binding Proteins; orphan nuclear receptor NGFI-B, 121479-42-3; Receptors, Cytoplasmic and Nuclear; Receptors, Steroid; RNA, Messenger; Sterol Regulatory Element Binding Protein 1; Transcription Factors; Triglycerides