Nur77 modulates hepatic lipid metabolism through suppression of SREBP1c activity

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 m...

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Bibliographic Details
Published in:Biochemical and biophysical research communications 2008-02, Vol.366 (4), p.910-916
Main Authors: Pols, Thijs W.H., Ottenhoff, Roelof, Vos, Mariska, Levels, Johannes H.M., Quax, Paul H.A., Meijers, Joost C.M., Pannekoek, Hans, Groen, Albert K., de Vries, Carlie J.M.
Format: Article
Language:English
Subjects:
60 APPLIED LIFE SCIENCES
Adenoviridae
Animals
CARBOXYLIC ACIDS
DNA-Binding Proteins - metabolism
Gene Expression Regulation
GENES
GLYCEROL
INHIBITION
Lipid Metabolism
LIVER
Liver - cytology
Liver - metabolism
Male
METABOLISM
MICE
Mice, Inbred C57BL
MITOCHONDRIA
NR4A nuclear receptors
NR4A1
Nuclear Receptor Subfamily 4, Group A, Member 1
Nur77
PHOSPHATES
RECEPTORS
Receptors, Cytoplasmic and Nuclear - metabolism
Receptors, Steroid - metabolism
RNA, Messenger - genetics
RNA, Messenger - metabolism
SREBP1c
Sterol Regulatory Element Binding Protein 1 - antagonists & inhibitors
Sterol regulatory element binding protein-1
STEROLS
Transcription Factors - metabolism
TRIGLYCERIDES
Triglycerides - blood
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Summary: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.
ISSN:0006-291X
1090-2104
DOI:10.1016/j.bbrc.2007.12.039