Liver X receptors at the intersection of lipid metabolism and atherogenesis

Lee, Stephen D.; Tontonoz, Peter

doi:10.1016/j.atherosclerosis.2015.06.042

Cited by 124 publications

(118 citation statements)

References 153 publications

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“…Intriguingly, the LXR-dependent regulation of ABCG1 expression was compromised in MΦ-IGF1R-KO macrophages. LXR is a major regulator of ABCG1 expression 89, 90 , in fact, LXR drives ABCG1 expression upon lipid-loading by modified LDL (which causes accumulation of oxysterols) 89, 90 . Thus impaired LXR regulation of ABCG1 expression could be an important mechanism underlying lowered cholesterol efflux in MΦ-IGF1R-KO macrophages.…”

Section: Discussionmentioning

confidence: 99%

Insulin-Like Growth Factor-1 Receptor Deficiency in Macrophages Accelerates Atherosclerosis and Induces an Unstable Plaque Phenotype in Apolipoprotein E–Deficient Mice

et al. 2016

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Background We have previously shown that systemic infusion of insulin-like growth factor-1 (IGF-1) exerts anti-inflammatory and anti-oxidant effects and reduces atherosclerotic burden in apolipoprotein E (Apoe) deficient mice. Monocytes/macrophages express high levels of IGF-1 receptor (IGF1R) and play a pivotal role in atherogenesis but the potential effects of IGF-1 on their function are unknown. Methods and Results To determine mechanisms whereby IGF-1 reduces atherosclerosis and to explore the potential involvement of monocytes/macrophages, we created monocyte/ macrophage specific IGF1R knockout (MΦ-IGF1R-KO) mice on Apoe−/− background. We assessed atherosclerotic burden, plaque features of stability, and monocyte recruitment to atherosclerotic lesions. Phenotypic changes of IGF1R-deficient macrophages were investigated in culture. MΦ-IGF1R-KO significantly increased atherosclerotic lesion formation, as assessed by Oil-red-O staining of en face aortae and aortic root cross-sections, and changed plaque composition to a less stable phenotype, characterized by increased macrophage and decreased α-smooth muscle actin-positive cell population, fibrous cap thinning, and decreased collagen content. Brachiocephalic artery lesions of MΦ-IGF1R-KO mice had histological features implying plaque vulnerability. Macrophages isolated from MΦ-IGF1R-KO mice showed enhanced proinflammatory responses upon stimulation by IFNγ and oxidized LDL and elevated antioxidant gene expression levels. Moreover, IGF1R deficient macrophages had decreased expression of ABCA1 and ABCG1 and reduced lipid efflux. Conclusions Our data indicate that macrophage IGF1R signaling suppresses macrophage and foam cell accumulation in lesions and reduces plaque vulnerability, providing a novel mechanism whereby IGF-1 exerts anti-atherogenic effects.

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Section: Discussionmentioning

confidence: 99%

Insulin-Like Growth Factor-1 Receptor Deficiency in Macrophages Accelerates Atherosclerosis and Induces an Unstable Plaque Phenotype in Apolipoprotein E–Deficient Mice

et al. 2016

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“…For example, in liver, the farnesoid X receptor (known as FXR or NR1H4), which binds bile acids and regulates genes involved in bile acid synthesis and transport, plays a major role in APOC2 gene transcription. In macrophages, however, key transcription factors for the APOC2 gene include the liver X receptor (LXR), whose role is to correct for cellular cholesterol 47, 48 and signal transducer and activator of transcription 1 (STAT1), which mediates cellular responses to interferons and certain cytokines and growth factors 49 . In intestine, ApoC2 gene expression increases with dietary lipids, as might be expected, but recent work in mice has also demonstrated a unique regulatory mechanism involving CD36 sensing of dietary fat 50 .…”

Section: Transcriptional Control Of the Human Apoc2 Genementioning

confidence: 99%

Apolipoprotein C-II: New findings related to genetics, biochemistry, and role in triglyceride metabolism

et al. 2017

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Apolipoprotein C-II (apoC-II) is a small exchangeable apolipoprotein found on triglyceride-rich lipoproteins (TRL), such as chylomicrons (CM) and very low-density lipoproteins (VLDL), and on high-density lipoproteins (HDL), particularly during fasting. ApoC-II plays a critical role in TRL metabolism by acting as a cofactor of lipoprotein lipase (LPL), the main enzyme that hydrolyses plasma triglycerides (TG) on TRL. Here, we present an overview of the role of apoC-II in TG metabolism, emphasizing recent novel findings regarding its transcriptional regulation and biochemistry. We also review the 24 genetic mutations in the APOC2 gene reported to date that cause hypertriglyceridemia (HTG). Finally, we describe the clinical presentation of apoC-II deficiency and assess the current therapeutic approaches, as well as potential novel emerging therapies.

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“…LXRs serve as cholesterol sensors and regulate cholesterol homeostasis. 86 Importantly, they also appear to be at the intersection of lipid metabolism and inflammation, as activation of LXRs has also been shown to modulate macrophage function and result in potent anti-inflammatory effects. 86,87 In a recent study of DR, a link between LXR expression in endothelial progenitor cells, critical for mediating vascular repair, and micro- and macrovascular complications was observed.…”

Section: Diabetic Retinopathymentioning

confidence: 99%

Rethinking Nuclear Receptors as Potential Therapeutic Targets for Retinal Diseases

Choudhary

Malek

2016

SLAS Discovery

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Collectively, retinal diseases, including age-related macular degeneration, retinitis pigmentosa, and diabetic retinopathy, result in severe vision impairment worldwide. The absence and/or limited availability of successful drug therapies for these blinding disorders necessitates further understanding their pathobiology and identifying new targetable signaling pathways. Nuclear receptors are transcription regulators of many key aspects of human physiology, as well as pathophysiology, with reported roles in development, aging, and disease. Some of the pathways regulated by nuclear receptors include, but are not limited to, angiogenesis, inflammation, and lipid metabolic dysregulation, mechanisms also important in the initiation and development of several retinal diseases. Herein, we present an overview of the biology of three diseases affecting the posterior eye, summarize a growing body of evidence that suggests direct or indirect involvement of nuclear receptors in disease progression, and discuss the therapeutic potential of targeting nuclear receptors for treatment.

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Liver X receptors at the intersection of lipid metabolism and atherogenesis

Cited by 124 publications

References 153 publications

Insulin-Like Growth Factor-1 Receptor Deficiency in Macrophages Accelerates Atherosclerosis and Induces an Unstable Plaque Phenotype in Apolipoprotein E–Deficient Mice

Insulin-Like Growth Factor-1 Receptor Deficiency in Macrophages Accelerates Atherosclerosis and Induces an Unstable Plaque Phenotype in Apolipoprotein E–Deficient Mice

Apolipoprotein C-II: New findings related to genetics, biochemistry, and role in triglyceride metabolism

Rethinking Nuclear Receptors as Potential Therapeutic Targets for Retinal Diseases

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