Deficiency of PXR decreases atherosclerosis in apoE-deficient mice

Sui, Yipeng; Xu, Jinxian; Rios-Pilier, Jennifer; Zhou, Changcheng

doi:10.1194/jlr.m017376

Cited by 77 publications

(65 citation statements)

References 49 publications

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“…PXR KO did not alter serum lipids but led to a reduction in macrophage CD36 expression and oxLDL uptake (1698). Chronic stimulation of PXR in apoE null mice decreased HDL and increased atherosclerosis with increased macrophage CD36 expression (2101).…”

Section: Arg1mentioning

confidence: 99%

Molecular Biology of Atherosclerosis

Hopkins

2013

Physiological Reviews

384

344

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At least 468 individual genes have been manipulated by molecular methods to study their effects on the initiation, promotion, and progression of atherosclerosis. Most clinicians and many investigators, even in related disciplines, find many of these genes and the related pathways entirely foreign. Medical schools generally do not attempt to incorporate the relevant molecular biology into their curriculum. A number of key signaling pathways are highly relevant to atherogenesis and are presented to provide a context for the gene manipulations summarized herein. The pathways include the following: the insulin receptor (and other receptor tyrosine kinases); Ras and MAPK activation; TNF-␣ and related family members leading to activation of NF-B; effects of reactive oxygen species (ROS) on signaling; endothelial adaptations to flow including G protein-coupled receptor (GPCR) and integrin-related signaling; activation of endothelial and other cells by modified lipoproteins; purinergic signaling; control of leukocyte adhesion to endothelium, migration, and further activation; foam cell formation; and macrophage and vascular smooth muscle cell signaling related to proliferation, efferocytosis, and apoptosis. This review is intended primarily as an introduction to these key signaling pathways. They have become the focus of modern atherosclerosis research and will undoubtedly provide a rich resource for future innovation toward intervention and prevention of the number one cause of death in the modern world.

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Section: Arg1mentioning

confidence: 99%

Molecular Biology of Atherosclerosis

Hopkins

2013

Physiological Reviews

384

344

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“…PXR, a xenobiotic-sensing receptor, up-regulates a large number of drugmetabolizing enzymes and transporters (Tolson and Wang, 2010;Wang et al, 2011). PXR has also been reported to be involved in lipid homeostasis and atherosclerosis (Sui et al, 2011). A recent study demonstrated that PXR activation induces tumor aggressiveness in humans and mice through increased cellular proliferation and drug resistance .…”

Section: Downloaded Frommentioning

confidence: 99%

RBCK1, an E3 Ubiquitin Ligase, Interacts with and Ubiquinates the Human Pregnane X Receptor

et al. 2012

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The pregnane X receptor (PXR, NR1I2) plays a pivotal role in the disposition and detoxification of numerous foreign and endogenous chemicals by increasing transcription of numerous target genes, including phase I and II drug-metabolizing enzymes and transporters. In the present study, yeast two-hybrid screening identified an E3 ubiquitin ligase, RBCK1 (Ring-B-box-coiled-coil protein interacting with protein kinase C-1), as a human pregnane X receptor (hPXR)-interacting protein. Coimmunoprecipitation studies confirmed the interaction between RBCK1 and hPXR when both were ectopically expressed in AD-293 cells. Domain mapping studies showed that the interaction between RBCK1 and hPXR involves all RBCK1 domains. We further demonstrate that RBCK1ubiquitinates hPXR, and this may target hPXR for degradation by the ubiquitin-proteasome pathway. Simultaneous ectopic overexpression of RBCK1 and PXR decreased PXR levels in AD-293 cells, and this decrease was inhibited by the proteasomal inhibitor MG-132 (carbobenzoxy-Leu-Leu-leucinal). Furthermore, overexpression of RBCK1 decreased endogenous levels of PXR in HepG2 cells. Of importance, ectopic overexpression and silencing of endogenous RBCK1 in primary human hepatocytes resulted in a decrease and increase, respectively, in endogenous PXR protein levels and in the induction of PXR target genes by rifampicin. These results suggest that RBCK1 is important for the ubiquitination of PXR and may play a role in its proteasomal degradation.

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“…PXR-apoE double knockout mice have a reduced atherosclerotic burden [41,42] and PXR-ob/ob mice or PXR knockouts on a high-fat diet show increased obesity and insulin resistance [43]. A strong note of caution must however be made when interpreting the PXR knockout mouse, as distinct functional differences are found between murine and human PXR in the humanized-PXR mouse and in animal models where pharmacological drug responses have been observed.…”

Section: Xenobiotic Receptorsmentioning

confidence: 99%

Nuclear Receptors in Vascular Biology

Bishop‐Bailey

2015

Curr Atheroscler Rep

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Nuclear receptors sense a diverse group of steroids and hormones (estrogens, progesterone, androgens, glucocorticoid and mineralocorticoid), vitamins (A and D), lipid metabolites, carbohydrates and xenobiotics. In response to these diverse but critically important mediators, nuclear receptors regulate the homeostatic control of lipids, carbohydrate, cholesterol and xenobiotic drug metabolism, inflammation, cell differentiation and development, including vascular development. The nuclear receptor family is one of the most important groups of signaling molecules in the body, and as such represent some of the most important established and emerging clinical and therapeutic targets. This review will highlight some of the emerging trends in nuclear receptor biology related to vascular biology.3

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Deficiency of PXR decreases atherosclerosis in apoE-deficient mice

Cited by 77 publications

References 49 publications

Molecular Biology of Atherosclerosis

Molecular Biology of Atherosclerosis

RBCK1, an E3 Ubiquitin Ligase, Interacts with and Ubiquinates the Human Pregnane X Receptor

Nuclear Receptors in Vascular Biology

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