Crosstalk between LXR and Toll-like Receptor Signaling Mediates Bacterial and Viral Antagonism of Cholesterol Metabolism

Castrillo, Antonio; Joseph, Sean B.; Vaidya, Sagar A.; Haberland, Margaret E.; Fogelman, Alan M.; Cheng, Genhong; Tontonoz, Peter

doi:10.1016/s1097-2765(03)00384-8

Cited by 444 publications

(376 citation statements)

References 59 publications

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“…34 Moreover, recent studies revealed that the LXR signaling pathway links innate immunity to macrophage cholesterol metabolism. 50 Thus, the ability of LXRs to promote reverse cholesterol transport, attenuate inflammation, and improve glucose tolerance identifies the LXR pathway as a potential target for novel therapeutic interventions in human cardiovascular disease. 38,51,52 In the present study, we demonstrate that LXR ligands attenuate cytokine-induced CRP expression in both Hep3B cells and PHHs.…”

Section: Discussionmentioning

confidence: 99%

A Nuclear Receptor Corepressor–Dependent Pathway Mediates Suppression of Cytokine-Induced C-Reactive Protein Gene Expression by Liver X Receptor

Blaschke

Takata

Caglayan

et al. 2006

Circulation Research

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Abstract-C-reactive protein (CRP), the prototypical human acute phase protein, is an independent risk predictor of future cardiovascular events, both in healthy individuals and in patients with known cardiovascular disease. In addition, previous studies indicate that CRP might have direct proatherogenic properties. Ligand activation of the liver X receptor (LXR), a member of the nuclear hormone receptor superfamily, inhibits inflammatory gene expression in macrophages and attenuates the development of atherosclerosis in various animal models. We demonstrate herein that 2 synthetic LXR ligands, T0901317 and GW3965, inhibit interleukin-1␤/interleukin-6 -induced CRP mRNA and protein expression in human hepatocytes. Knockdown of LXR␣/␤ by short interfering RNAs completely abolished the inhibitory effect of the LXR agonist T0901317 on cytokine-induced CRP gene transcription. Transient transfection experiments with 5Ј-deletion CRP promoter constructs identified a region from Ϫ125 to Ϫ256 relative to the initiation site that mediated the inhibitory effect of LXR ligands on CRP gene transcription. Depletion of the nuclear receptor corepressor by specific short interfering RNA increased cytokine-inducible CRP mRNA expression and promoter activity and reversed LXR ligand-mediated repression of CRP gene transcription. Chromatin immunoprecipitation assays indicated that nuclear receptor corepressor is present on the endogenous CRP promoter under basal conditions. Cytokine-induced clearance of nuclear receptor corepressor complexes was inhibited by LXR ligand treatment, maintaining the CRP gene in a repressed state. Finally, treatment of C57Bl6/J mice with LXR ligands attenuated lipopolysaccharide-induced mouse CRP and serum amyloid P component gene expression in the liver, whereas no effect was observed in LXR␣␤ knockout mice. Our observations identify a novel mechanism of inflammatory gene regulation by LXR ligands. Thus, inhibition of CRP expression by LXR agonists may provide a promising approach to impact initiation and progression of atherosclerosis. (Circ Res. 2006;99:e88-e99.)

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Section: Discussionmentioning

confidence: 99%

A Nuclear Receptor Corepressor–Dependent Pathway Mediates Suppression of Cytokine-Induced C-Reactive Protein Gene Expression by Liver X Receptor

Blaschke

Takata

Caglayan

et al. 2006

Circulation Research

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“…LXRs have been implicated in the regulation of cholesterol metabolism and clearance [21,22] and recently in inflammation [23,24]. Mice lacking LXR-a lose their ability to respond normally to dietary cholesterol and are unable to tolerate any amount of cholesterol in excess of that they synthesize de novo [25][26][27].…”

Section: Lipid Metabolism Of Lesion Macrophages: the Pros And Cons Fomentioning

confidence: 99%

Nuclear receptors in macrophages: A link between metabolism and inflammation

Szántó

Röszer

2007

FEBS Letters

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Subclinical inflammation is a candidate etiological factor in the pathogenesis of metabolic syndrome and in the progression of atherosclerosis. A central role for activated macrophages has been elucidated recently as important regulators of the inflammatory process in atherosclerosis. Macrophage differentiation and function can be modulated by a class of transcription factors termed nuclear receptors. These are activated by intermediary products of basic metabolic processes. In this review the contribution of peroxisome proliferator-activated receptors and liver X receptors to macrophage functions in inflammation and lipid metabolism will be discussed in light of their roles in macrophages during atherosclerosis.In the past decade much effort has been made to understand the mechanisms how lipids are handled by macrophages and how inflammation could promote the atherogenic process. Here, we also provide an overview of these two fields.

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“…In macrophages, LXR activation inhibits the expression of inflammatory cytokines (i.e. IL-1β, IL-6 and TNFα) [20,21], monocyte chemoattractant protein and osteopontin [22]. Unfortunately, first-generation LXR agonists (T0901317, GW3965) caused hypertriacylglycerolaemia through upregulation of hepatic sterol regulatory element-binding protein 1c (SREBP1c) [23].…”

Section: Introductionmentioning

confidence: 99%

Liver X receptors preserve renal glomerular integrity under normoglycaemia and in diabetes in mice

et al. 2013

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Aims/hypothesis Liver X receptors (LXRs) α and β are nuclear hormone receptors that are widely expressed in the kidney. They promote cholesterol efflux from cells and inhibit inflammatory responses by regulating gene transcription. Here, we hypothesised (1) that LXR deficiency would promote renal decline in a mouse model of diabetes by accelerating intraglomerular cholesterol accumulation and, conversely, (2) that LXR agonism would attenuate renal decline in diabetes.Methods Diabetes was induced with streptozotocin (STZ) and maintained for 14 weeks in Lxrα/β +/+ (Lxrα, also known as Nr1h3; Lxrβ, also known as Nr1h2) and Lxrα/β −/− mice. In addition, STZ-injected DBA/2J mice were treated with vehicle or the LXR agonist N ,N -dimethyl-hydroxycholenamide (DMHCA) (80 mg/kg daily) for 10 weeks. To determine the role of cholesterol in diabetic nephropathy (DN), mice were placed on a Western diet after hyperglycaemia developed. Results Even in the absence of diabetes, Lxrα/β −/− mice exhibited a tenfold increase in the albumin:creatinine ratio and a 40-fold increase in glomerular lipid accumulation compared with Lxrα/β +/+ mice. When challenged with diabetes, Lxrα/β −/− mice showed accelerated mesangial matrix expansion and glomerular lipid accumulation, with upregulation of inflammatory and oxidative stress markers. In the DN-sensitive STZ DBA/2J mouse model, DMHCA treatment significantly decreased albumin and nephrin excretion (by 50% each), glomerular lipids and plasma triacylglycerol (by 70%) and cholesterol (by 48%); it also decreased kidney inflammatory and oxidative stress markers compared with vehicle-treated mice. Conclusions/interpretation These data support the idea that LXR plays an important role in the normal and diabetic kidney, while showing that LXR, through its inhibitory effect on inflammation and cholesterol accumulation in glomeruli, could also be a novel therapeutic target for DN.

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Crosstalk between LXR and Toll-like Receptor Signaling Mediates Bacterial and Viral Antagonism of Cholesterol Metabolism

Cited by 444 publications

References 59 publications

A Nuclear Receptor Corepressor–Dependent Pathway Mediates Suppression of Cytokine-Induced C-Reactive Protein Gene Expression by Liver X Receptor

A Nuclear Receptor Corepressor–Dependent Pathway Mediates Suppression of Cytokine-Induced C-Reactive Protein Gene Expression by Liver X Receptor

Nuclear receptors in macrophages: A link between metabolism and inflammation

Liver X receptors preserve renal glomerular integrity under normoglycaemia and in diabetes in mice

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