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
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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.

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Available from: Paul Hubertus Andreas Quax, Sep 28, 2015
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    • "Previously, NR4A1 was reported to modulate lipid metabolism in the liver (Pols et al., 2008), as both triglyceride and cholesterol content was reduced by NR4A1, most likely through reduced lipid uptake (Zhang et al., 2012). However, in the NR4A1 knockdown Huh7.5.1 cell line, we did not observe significant changes in quantity or size of lipid droplets, which are triglyceride and cholesterol storage organelles and the lipid source for VLDL formation (Gibbons et al., 2000). "
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    ABSTRACT: The orphan nuclear receptor subfamily 4 group A member 1 (NR4A1) is a transcription factor stimulated by many factors and plays pivotal roles in metabolism, proliferation, and apoptosis. The expression of NR4A1 in Huh7.5.1 cells was significantly upregulated by HCV infection. The silencing of NR4A1 inhibited the entry of HCV and reduced the specific infectivity of secreted HCV particles, but had only minor or no effect on the genome replication and translation, virion assembly, and viral release steps of the virus life cycle. Further experiments demonstrated that the silencing of NR4A1 affected virus entry through pan-downregulation of the expression of HCV receptors SR-BI, Occludin, Claudin-1, and EGFR, but not CD81. The reduced specific infectivity of HCV in the knockdown cells was due to the decreased apolipoprotein E (ApoE) expression. These results explained the delayed spread of HCV in NR4A1 knockdown Huh7.5.1 cells. Thus, NR4A1 plays a role in HCV replication through regulating the expression of HCV receptors and ApoE and facilitates HCV entry and spread.
    Journal of General Virology 04/2014; 95(Pt_7). DOI:10.1099/vir.0.065003-0 · 3.18 Impact Factor
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    • "+ indicates significant evidence for antidiabetic effects, −, evidence for deleterious effects, ?, no evidence, or suggestive but inconclusive evidence. PPARs (Barish et al., 2006; Lalloyer and Staels, 2010; Lehrke and Lazar, 2005); ERα (Bryzgalova et al., 2008b; Mauvais-Jarvis, 2011); CAR (Dong et al., 2009; Lahtela et al., 1985; Sotaniemi and Karvonen, 1989); FXR (Cipriani et al., 2010; Sanyal et al., 2009; Watanabe et al., 2006; Zhang et al., 2006); HNF-4α (* revealed by impact of MODY mutations in humans (Vaxillaire and Froguel, 2008) and pancreatic knockouts in mice (Gupta et al., 2005; Miura et al., 2006)), VDR (Takiishi et al., 2010); TRβ (Amorim et al., 2009; Bryzgalova et al., 2008a); LRH-1 (Lee et al., 2011); LXRα/β (Cao et al., 2003; Commerford et al., 2007; Grefhorst et al., 2005; Herzog et al., 2007; Laffitte et al., 2003; Liu et al., 2006); NR4A (Chao et al., 2009; Pols et al., 2008) (note – NR4A effects are based on induction or loss of receptor expression rather than ligand responses). "
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    ABSTRACT: Several pathways and pathologies have been suggested as connections between obesity and diabetes, including inflammation of adipose and other tissues, toxic lipids, endoplasmic reticulum stress, and fatty liver. One specific proposal is that insulin resistance induces a vicious cycle in which hyperinsulinemia increases hepatic lipogenesis and exacerbates fatty liver, in turn further increasing insulin resistance. Here I suggest that reversing this cycle via suppression of the lipogenic transcription factor SREBP-1c is a common thread that connects the antidiabetic effects of a surprising number of nuclear hormone receptors, including CAR, LRH-1, TRβ, ERα, and FXR/SHP.
    Cell metabolism 05/2012; 15(5):615-22. DOI:10.1016/j.cmet.2012.03.016 · 17.57 Impact Factor
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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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    ABSTRACT: Dyslipidemia and atherosclerosis are associated with reduced insulin sensitivity and diabetes, but the mechanism is unclear. Gain of function of the gene encoding deacetylase SirT1 improves insulin sensitivity and could be expected to protect against lipid abnormalities. Surprisingly, when transgenic mice overexpressing SirT1 (SirBACO) are placed on atherogenic diet, they maintain better glucose homeostasis, but develop worse lipid profiles and larger atherosclerotic lesions than controls. We show that transcription factor cAMP response element binding protein (Creb) is deacetylated in SirBACO mice. We identify Lys136 is a substrate for SirT1-dependent deacetylation that affects Creb activity by preventing its cAMP-dependent phosphorylation, leading to reduced expression of glucogenic genes and promoting hepatic lipid accumulation and secretion. Expression of constitutively acetylated Creb (K136Q) in SirBACO mice mimics Creb activation and abolishes the dyslipidemic and insulin-sensitizing effects of SirT1 gain of function. We propose that SirT1-dependent Creb deacetylation regulates the balance between glucose and lipid metabolism, integrating fasting signals.
    Cell metabolism 11/2011; 14(6):758-67. DOI:10.1016/j.cmet.2011.10.007 · 17.57 Impact Factor
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