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: 2.41). 02/2008; 366(4):910-6. DOI:10.1016/j.bbrc.2007.12.039
Source: PubMed

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.

0 0
  • Source
    [show abstract] [hide abstract]
    ABSTRACT: Since it is associated to the obesity epidemic, Non Alcoholic Fatty Liver Disease (NAFLD) has become a major public health issue. NAFLD ranges from benign hepatic steatosis, ie abnormally elevated triglyceride accumulation, to Non Alcoholic Steatohepatitis (NASH) that can lead to irreversible liver damages. The search for pharmacological and dietary approaches to treat or prevent NAFLD has pointed at nuclear receptors as sensible targets. Indeed, nuclear receptors are ligand-sensitive transcription factors that play a central role in hepatic lipid metabolism. Among nuclear receptors, the Liver X Receptor has been identified as an oxysterol receptor. It is involved in the control of various aspects of lipid metabolism that are reviewed in this manuscript. We highlight the role of LXR in the gut-liver axis and the studies that have provided a rationale for strategies specifically targeting the hepatic activity of LXR in NAFLD.
    Biochemical pharmacology 03/2013; · 4.25 Impact Factor
  • [show abstract] [hide abstract]
    ABSTRACT: It is clear that lipid disorder and inflammation are associated with cardiovascular diseases and underlying atherosclerosis. Nur77 has been shown to be involved in inflammatory response and lipid metabolism. Here, we explored the role of Nur77 in atherosclerotic plaque progression in apoE(-/-) mice fed a high-fat/high cholesterol diet. The Nur77 gene, a nuclear hormone receptor, was highly induced by treatment with Cytosporone B (Csn-B, specific Nur77 agonist), recombinant plasmid over-expressing Nur77 (pcDNA-Nur77), while inhibited by treatment with siRNAs against Nur77 (si-Nur77) in THP-1 macrophage-derived foam cells, HepG2 cells and Caco-2 cells, respectively. In addition, the expression of Nur77 was highly induced by Nur77 agonist Csn-B, lentivirus encoding Nur77 (LV-Nur77), while silenced by lentivirus encoding siRNA against Nur77 (si-Nur77) in apoE(-/-) mice fed a high-fat/high cholesterol diet, respectively. We found that increased expression of Nur77 reduced macrophage-derived foam cells formation and hepatic lipid deposition, downregulated gene levels of inflammatory molecules, adhesion molecules and intestinal lipid absorption, and decreases atherosclerotic plaque formation. These observations provide direct evidence that Nur77 is an important nuclear hormone receptor in regulation of atherosclerotic plaque formation and thus represents a promising target for the treatment of atherosclerosis.
    PLoS ONE 01/2014; 9(1):e87313. · 3.73 Impact Factor
  • [show abstract] [hide abstract]
    ABSTRACT: Type 2 diabetes mellitus is a disorder characterized by insulin resistance and a relative deficit in insulin secretion, both of which result in elevated blood glucose. Understanding the molecular mechanisms underlying the pathophysiology of diabetes could lead to the development of new therapeutic approaches. An ever-growing body of evidence suggests that members of the NR4A family of nuclear receptors could play a pivotal role in glucose homoeostasis. This review aims to present and discuss advances so far in the evaluation of the potential role of NR4A in the regulation of glucose homoeostasis and the development of type 2 diabetes.
    Diabetes & Metabolism 09/2013; · 2.39 Impact Factor

Full-text (3 Sources)

Available from
Dec 6, 2012