Identification of macrophage liver X receptors as inhibitors of atherosclerosis

Tangirala, Rajendra K.; Bischoff, Eric D.; Joseph, Sean B.; Wagner, Brandee; Walczak, Robert; Laffitte, Bryan; Daige, Chris; Thomas, Diane; Heyman, Richard A.; Mangelsdorf, David J.; Wang, Xuping; Lusis, Aldons J.; Tontonoz, Peter; Schulman, Ira G.

doi:10.1073/pnas.182199799

Cited by 411 publications

(354 citation statements)

References 27 publications

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“…24 Transplantation of bone marrow cells containing hematopoietic stem cells (HSCs) transduced with lentiviral vectors carrying a synthetic macrophage promoter-driving expression of the mouse LXRa cDNA caused a significant reduction of both atherosclerotic lesions and plasma triglyceride levels through expression of the transgene in BMDMs. These results are consistent with the observation that loss of LXR expression in bone marrow and peripheral blood cells increases atherosclerosis, 5 supporting the notion that the macrophage is a primary vehicle for the antiatherogenic effects of LXR, and showing the therapeutic potential of delivery of LXR via HSC-derived macrophages.…”

Section: Discussionsupporting

confidence: 89%

“…Apolipoprotein E-deficient (apoE À/À ) or low-density lipoprotein receptor-deficient (LDLR À/À ) mice transplanted with bone marrow cells from LXRa/b double-knockout (LXRa/b À/À ) animals exhibited significantly greater atherosclerotic lesion development than their counterparts receiving bone marrow cells from wild-type mice. 5 In addition, LXRa/b À/À mice exhibit increased cholesterol accumulation in arterial wall macrophages even on normal chow diets. Consistently, activation of LXRs by synthetic agonists provides protection against lesion development and leads to regression of established lesions in mouse models.…”

Section: Introductionmentioning

confidence: 99%

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Macrophage LXRα gene therapy ameliorates atherosclerosis as well as hypertriglyceridemia in LDLR−/− mice

Biju

Xu³

et al. 2011

Gene Ther

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Liver X receptors (LXRs) are implicated in the regulation of cholesterol homeostasis, inflammatory response and atherogenesis. Administration of LXR agonists inhibits the progress of atherosclerosis, and also increases plasma triglyceride levels, representing an obstacle to their use in treating this disease. The objective of this study was to develop an alternative approach that could overcome this obstacle. Eight-week-old low-density lipoprotein receptor-deficient (LDLR À/À ) mice were transplanted with hematopoietic stem cell (HSC)-enriched bone marrow cells transduced with lentivectors expressing either green fluorescent protein (GFP) (Lenti-SP-GFP, control) or LXRa (Lenti-SP-LXRa) driven by a synthetic macrophage promoter. At 4 weeks post-transplant, the mice were fed with a Western diet for 8 weeks and then killed. Compared with Lenti-SP-GFP mice, the Lenti-SP-LXRa mice had a 30% reduction in atherosclerotic lesions, which was accompanied by increases in levels of macrophage expression of cholesterol efflux genes apolipoprotein E and ATP-binding cassette A1, as well as decreases in plasma inflammatory cytokines interleukin-6 and tumor necrosis factor-a. Intriguingly, a 50% reduction of plasma triglyceride level was also observed. We conclude that HSC-based macrophage LXRa gene therapy ameliorates the development of atherosclerosis along with an unexpected concomitant reduction of plasma triglyceride levels in LDLR À/À mice. These findings highlight the potential value of macrophage LXR expression as an avenue for therapeutic intervention against atherosclerosis.

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Section: Discussionsupporting

confidence: 89%

Section: Introductionmentioning

confidence: 99%

Macrophage LXRα gene therapy ameliorates atherosclerosis as well as hypertriglyceridemia in LDLR−/− mice

Biju

Xu³

et al. 2011

Gene Ther

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“…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. This effect is, at least partially, mediated by inhibition of NCoR clearance from the CRP promoter, which prevents the switch from active repression to transcriptional activation.…”

Section: Discussionmentioning

confidence: 51%

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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“…The ability of cells to unload excess cholesterol is dramatically reduced in mice lacking LXRs, leading to cholesterol accumulation in multiple tissues (44)(45)(46). The role of LXRs in the CNS is less well understood.…”

Section: Discussionmentioning

confidence: 99%

Attenuation of neuroinflammation and Alzheimer's disease pathology by liver x receptors

Zelcer

Khanlou

Clare

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

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224

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Alzheimer's disease (AD) is an age-dependent neurodegenerative disease that causes progressive cognitive impairment. The initiation and progression of AD has been linked to cholesterol metabolism and inflammation, processes that can be modulated by liver x receptors (LXRs). We show here that endogenous LXR signaling impacts the development of AD-related pathology. Genetic loss of either Lxr␣ or Lxr␤ in APP/PS1 transgenic mice results in increased amyloid plaque load. LXRs regulate basal and inducible expression of key cholesterol homeostatic genes in the brain and act as potent inhibitors of inflammatory gene expression. Ligand activation of LXRs attenuates the inflammatory response of primary mixed glial cultures to fibrillar amyloid ␤ peptide (fA␤) in a receptordependent manner. Furthermore, LXRs promote the capacity of microglia to maintain fA␤-stimulated phagocytosis in the setting of inflammation. These results identify endogenous LXR signaling as an important determinant of AD pathogenesis in mice. We propose that LXRs may be tractable targets for the treatment of AD due to their ability to modulate both lipid metabolic and inflammatory gene expression in the brain.T he liver x receptors ␣ and ␤ (LXR␣/NR1H3 and LXR␤/ NR1H2, respectively) are oxysterol-activated nuclear receptors that play an important role in the control of cellular and whole-body cholesterol homeostasis (1-4). LXRs are also potent inhibitors of inflammatory responses in macrophages, pointing to an additional function for LXR signaling in immune regulation (5-11). The function of LXRs in the brain is not well understood. Ligand activation of LXRs promotes cholesterol efflux from glia (12, 13) and primary neurons (14), whereas mice deficient in expression of Lxr␣ and Lxr␤ develop marked accumulation of neutral lipids in the brain (15). Functionally, loss of LXR␤ leads to adult-onset motor neuron degeneration by the age of 7 months (16). The role of LXRs in human neurodegenerative diseases, however, remains largely unknown.Alzheimer's disease (AD) is an age-dependent neurodegenerative disease typified by progressive neuronal loss and cognitive impairment. AD is characterized by extraneuronal deposits of ␤-amyloid (A␤) fibrils (fA␤) (17) and intraneuronal tangles of hyperphosphorylated (18). The identification of rare mutations in the amyloid precursor protein (APP) and in presenilin genes (PS) in human AD is consistent with a central role for A␤ in AD pathogenesis (19). AD is a multifactorial disease, and inflammatory processes and cholesterol metabolism are among several factors that have been linked to its etiology.The AD brain exhibits prominent activation of innate immune responses. For example, elevated levels of inflammatory mediators can be measured in AD brains, and these are postulated to contribute to neuronal loss. The local inflammatory response is mediated by activated microglia and reactive astrocytes that surround the senile plaques (20,21). Interaction of microglia with fA␤ leads to their activation and the release of an arra...

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Identification of macrophage liver X receptors as inhibitors of atherosclerosis

Cited by 411 publications

References 27 publications

Macrophage LXRα gene therapy ameliorates atherosclerosis as well as hypertriglyceridemia in LDLR−/− mice

Macrophage LXRα gene therapy ameliorates atherosclerosis as well as hypertriglyceridemia in LDLR−/− mice

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

Attenuation of neuroinflammation and Alzheimer's disease pathology by liver x receptors

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