Nur77 modulates hepatic lipid metabolism through suppression of SREBP1c activity

Medical Biochemistry, Academic Medical Center, Meibergdreef 15, 1105 AZ Amsterdam, The Netherlands.
Biochemical and Biophysical Research Communications (Impact Factor: 2.3). 02/2008; 366(4):910-6. DOI: 10.1016/j.bbrc.2007.12.039
Source: PubMed


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.

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Available from: Paul Hubertus Andreas Quax
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    • "Expression of most Creb target genes was lower, consistent with decreased Creb activity. Thus, levels of Insulin receptor substrate-2 (Irs2) and Nur77, a gene that promotes gluconeogenesis and inhibits lipogenesis (Chao et al., 2007; Pols et al., 2008), decreased, as did mRNA levels encoding Nur77 (encoded by Nr4a1), Irs2, Igfbp1, and neuron-derived orphan receptor-1 Nor1 (encoded by Nr4a3). Pparγ, a target of Creb-dependent suppression (Herzig et al., 2003) showed increased levels, consistent with decreased Creb activity (Figure 3A). "
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