Novel Functions of PXR in Cardiometabolic Disease☆

BBAGRM-00998; No. of pages: 9; 4C: 5 Biochimica et Biophysica Acta xxx (2016) xxx–xxx

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Biochimica et Biophysica Acta

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Novel functions of PXR in cardiometabolic disease☆

Changcheng Zhou ⁎

Department of Pharmacology and Nutritional Sciences, University of Kentucky, Lexington, KY 40536, USA Saha Cardiovascular Research Center, University of Kentucky, Lexington, KY 40536, USA article info abstract

Article history: Cardiometabolic disease emerges as a worldwide epidemic and there is urgent need to understand the molecular Received 22 December 2015 mechanisms underlying this chronic disease. The chemical environment to which we are exposed has signiﬁcant- Received in revised form 18 February 2016 ly changed in the past few decades and recent research has implicated its contribution to the development of Accepted 19 February 2016 many chronic human diseases. However, the mechanisms of how exposure to chemicals contributes to the devel- Available online xxxx opment of cardiometabolic disease are poorly understood. Numerous chemicals have been identiﬁed as ligands

Keywords: for the pregnane X receptor (PXR), a nuclear receptor functioning as a xenobiotic sensor to coordinately regulate Xenobiotic receptor xenobiotic metabolism via transcriptional regulation of xenobiotic-detoxifying enzymes and transporters. In the Cardiovascular disease past decade, the function of PXR in the regulation of xenobiotic metabolism has been extensively studied by Obesity many laboratories and the role of PXR as a xenobiotic sensor has been well-established. The identiﬁcation of Metabolic disorders PXR as a xenobiotic sensor has provided an important tool for the study of new mechanisms through which Lipid homeostasis xenobiotic exposure impacts human chronic diseases. Recent studies have revealed novel and unexpected Endocrine disrupting chemicals roles of PXR in modulating obesity, insulin sensitivity, lipid homeostasis, atherogenesis, and vascular functions. These studies suggest that PXR signaling may contribute signiﬁcantly to the pathophysiological effects of many known xenobiotics on cardiometabolic disease in humans. The discovery of novel functions of PXR in cardiometabolic disease not only contributes to our understanding of “gene–environment interactions” in predisposing individuals to chronic diseases but also provides strong evidence to inform future risk assessment for relevant chemicals. This article is part of a Special Issue entitled: Xenobiotic nuclear receptors. © 2016 Elsevier B.V. All rights reserved.

1. Introduction

Cardiometabolic disease, which includes obesity, cardiovascular disease (CVD), hypertension, and type 2 diabetes, is a rapidly growing Abbreviations: ABCA, ATP-binding cassette transporter; Apo, Apolipoprotein; ARV, epidemic representing a serious health threat in an increasing number Anti-retroviral; BPA, Bisphenol A; CAR, Constitutive androstane receptor; CETP, of countries. There is an urgent need to understand the mechanisms un- Cholesteryl ester transfer protein; CPT1, Carnitine palmitoyltransferase 1; CREB, cAMP re- derlying cardiometabolic disease. While considerable progress has been sponse element-binding protein; CVD, Cardiovascular disease; CYP, Cytochrome P450; DBD, DNA-binding domain; DEHP, Di(2-ethylhexyl)phthalate; DGAT, Diglyceride acyl- achieved to identify gene variations contributing to cardiometabolic transferase; EC, Endothelia cell; EDC, Endocrine disrupting chemicals; FAC, Fatty acid disease, the role played by “gene–environment interactions” in elongase; FoxO1, Forkhead box protein O1; FoxA2, Forkhead box protein A2; FXR, predisposing individuals to cardiometabolic disease remains relatively Farnesoid X receptor; G-6-P, Glucose-6-phosphatase; GST, Glutathione transferase; HFD, unexplored. In addition to the obvious contributions of diet and lifestyle High-fat diet; HDL, High-density lipoproteins; HMGCS2, 3-hydroxy-3-methylglutartate- CoA synthase 2; HNF4α, Hepatocyte nuclear factor 4α; JNK, c-Jun N-terminal kinase; on human health, the chemical environment to which we are exposed LBD, Ligand-binding domain; LDL, Low-density lipoprotein; LDLR, LDL receptor; LipA, has signiﬁcantly changed in the past few decades and has recently Lysosomal lipase; LipF, Gastric lipase; MDR1, Multidrug resistance 1; MRP1, Multidrug been implicated in the etiology of cardiometabolic disease. However, resistance-associated protein 1; NPC1L1, Niemann-Pick C1-Like 1; PCB, Polychlorinated bi- the mechanisms of how exposure to chemicals contribute to the devel- α phenyl; PEPCK1, Phosphoenolpyruvate carboxykinase 1; PCN, Pregnenolone 16 - opment of chronic human diseases such as cardiometabolic disease are carbonitrile; PPAR, Peroxisome proliferator-activated receptor; PXR, Pregnane X receptor; PXRE, PXR response element; RIF, Rifampicin; RXR, Retinoid X receptor; SCD-1, Stearoyl- poorly understood. CoA desaturase-1; SFN, Sulforaphane; SMC, Smooth muscle cell; SXR, Steroid and xenobi- To sense and respond to environmental chemicals, mammals have otic receptor; TBC, Tributyl citrate; VLDL, Very low-density lipoproteins; WAT, White adi- evolved a defensive network governed by xenobiotic receptors such as pose tissue; WT, Wild type. the pregnane X receptor (PXR; also known as steroid and xenobiotic ☆ This article is part of a Special Issue entitled: Xenobiotic nuclear receptors. – ⁎ Department of Pharmacology and Nutritional Sciences, University of Kentucky, 900 receptor, or SXR; NR1I2 for standard nomenclature) [1 5]. PXR func- South Limestone, 517 Wethington Bldg., Lexington, KY 40536, USA. tions as a xenobiotic sensor that induces the expression of genes re- E-mail address: [email protected]. quired for xenobiotic metabolism in the liver and intestine, including

Please cite this article as: C. Zhou, Novel functions of PXR in cardiometabolic disease, Biochim. Biophys. Acta (2016), http://dx.doi.org/10.1016/ j.bbagrm.2016.02.015 2 C. Zhou / Biochimica et Biophysica Acta xxx (2016) xxx–xxx

Table 1 sharing only ~60–80% identity compared with the ~90% typically exhib- Summary of genes directly or indirectly regulated by PXR and their functions in cardio- ited by orthologous nuclear receptors [5].Further,PXRalsoexhibits metabolic disease. significant differences in its pharmacology across species (e.g., mouse Organ/cell type Function Gene Reference vs. human) [1,5,12,13]. For example, the antibiotic rifampicin and Liver Cholesterol and lipid CD36 [48,76,77] plastic base chemical bisphenol A (BPA) are potent activators of metabolism FAS [48,76] human and rabbit PXR, but do not affect mouse or rat PXR activity SCD-1 [48,74,76] [12,14]. By contrast, the synthetic steroid pregnenolone-16α- ACC-1 [48] carbonitrile (PCN) is a potent agonist of rat and mouse PXR but does PPARγ [48,77] SREBP1a [148] not activate human or rabbit PXR [12,15,16]. The unique feature of S14 [52] PXR also explains species-specific differences in xenobiotic induction Lipin-1 [39] by CYP3A. Despite its diverse LBD, the DNA-binding domain (DBD) of SLC13A5 [75] PXR is well conserved with 95% amino acid sequence homology across AKR1B10 [148] various species and PXR target genes appear to be identical in humans Insig-1 [149] fi HMGCS2 [45] and mice [4,5]. In addition to its species-speci c responses, some CPT1a [45] ligands can also activate PXR and regulate its target genes in a tissue- CYP7A1 [69,70] specific manner [17–19]. For example, rifaximin, a clinically used DHCR24 [150] nonsynthetic antibiotic, has been identified to be an intestine-specific Lipoprotein metabolism ApoA-I [78–80] ApoA-IV [63] agonist for the human PXR [18]. Tocotrienol forms of vitamin E can ABCA-1 [79,80,151] selectively regulate the PXR target genes in hepatic and intestinal cell HL [51,80] lines, which may be due to different expression levels of nuclear recep- SR-B1 [51,80,151] tor co-repressor in hepatic and intestinal cells [17]. These results Glucose metabolism PEPCK1 [41,152] indicate that PXR mediate species- and tissue-specific responses to G-6-P [41,44,152] Glucokinase [53,54] xenobiotic exposure. Intestine Cholesterol and lipid CD36 [50,86,92] Since it was first identified in 1998, the functions of PXR in drug and metabolism NPC1L1 [92] xenobiotic metabolism have been extensively studied by many labora- DGAT1 [50,86] tories. To date, the role of PXR as a xenobiotic sensor has been well- DGAT2 [50,86] FABP2 [50] established and PXR has been considered as a master regulator of LipA [86] xenobiotic metabolism. The identification of PXR as a xenobiotic sensor LipF [86] has provided an important tool for the study of new mechanisms CYP27A1 [89,90] through which xenobiotic exposure impacts diseases. Recent studies ABCA1 [89] have revealed novel functions of PXR beyond xenobiotic metabolism Immune cells (T cells, B Inflammation and CD36 [63,119,129] cells, and macrophages) atherosclerosis CD25 [108] and this review focuses its functions in cardiometabolic disease (See IFN-γ [108] Table 1). IL-10 [108] α TNF [113] 2. Role of PXR in obesity and insulin resistance COX2 [113] Vasculature and vascular Inflammation and TNFα [143] cells (ECs and SMCs) atherosclerosis VCAM-1 [143] The prevalence of obesity has more than doubled over the past E-selectin [143] 30 years and 60 million people are currently defined as obese in the NLRP3 [144] United States alone. If current trends continue, more than half of the β IL-1 [144] United States population could be obese by 2030 [20]. Obesity is an in- Detoxification and CYP3A23 [142] oxidative stress GSTM1 [142] dependent risk factor for insulin resistance, type 2 diabetes, and athero- protection GSTM4 [144] sclerotic CVD, the leading causes of death worldwide [21,22].Itis MDR1 [144] generally accepted that environmental factors, most notably consump- MRP2 [142] tion of a palatable high-fat diet (HFD), have contributed to the rapidly escalating prevalence of obesity and associated metabolic dysfunctions. Recent findings have implicated exposure to certain chemicals such as cytochrome P450 (CYP) enzymes (e.g. CYP3A4), conjugating enzymes endocrine disrupting chemicals (EDCs) in the etiology of obesity and (e.g. glutathione transferase [GST]), and ABC family transporters (e.g. metabolic disorders [23–30]. Mounting evidence demonstrates that multidrug resistance 1 [MDR1]) [4–6]. Many of PXR-regulated metabo- many xenobiotics such as EDCs can interfere with complex endocrine lizing enzymes and transporters play a central role in xenobiotic metab- signaling mechanisms and result in adverse consequences in humans olism. For instance, PXR is a key transcriptional factor that regulates the and wildlife [26,31–33]. Numerous EDCs, including organochlorine expression of CYP3A4, which is responsible for the metabolism of more and organophosphate pesticides, alkylphenols, phthalates (e.g. di(2- than 50% of clinically used drugs in humans [7]. In addition to PXR, ethylhexyl)phthalate [DEHP]), polychlorinated biphenyls (PCBs), another xenobiotic receptor, constitutive androstane receptor (CAR; bisphenol A (BPA), and its analogs (e.g. BPB, BPAF) have been identified NR1I3 for standard nomenclature) also has a broad role in xenobiotic to activate PXR [5,14,16,34,35]. PXR may play a significant role in metabolism [8]. Unlike PXR, CAR shows relatively high basal activity mediating the pathophysiological effects of those known EDCs and to activate target genes without ligand. PXR and CAR also can regulate other chemicals in humans and animals. Indeed, recent studies have overlapped and distinctive sets of genes involved in xenobiotic metabo- uncovered novel functions of PXR in obesity and insulin resistance. lism [9–11]. It has long been suspected that PXR signaling is involved in the reg- Interestingly, numerous compounds including endogenous hor- ulation of glucose homeostasis as many clinically relevant PXR-agonistic mones, dietary steroids, pharmaceutical agents, and xenobiotic drugs can affect blood glucose levels [36–39]. For example, rifampicin, chemicals have been identified to be ligands of PXR [1,4–6]. The diverse phenytoin, and cyclophosphamide which are all PXR ligands have ligand-binding properties of PXR are facilitated by the large volume and been documented to induce hyperglycemia in patients [36–38].Bycon- smooth shape of its ligand-binding pocket in the ligand-binding domain trast, long-term treatment with another PXR ligand, phenobarbital, can (LBD). Compared with most other nuclear receptors including CAR, PXR reduce plasma glucose levels and improve insulin sensitivity in diabetic is remarkably divergent across mammalian species with the LBDs patients [40]. By performing mammalian cell-based two-hybrid

Please cite this article as: C. Zhou, Novel functions of PXR in cardiometabolic disease, Biochim. Biophys. Acta (2016), http://dx.doi.org/10.1016/ j.bbagrm.2016.02.015 C. Zhou / Biochimica et Biophysica Acta xxx (2016) xxx–xxx 3 screening, Kodama et al. [41] revealed an important role of PXR in the which could lead to increased energy expenditure [53]. Interestingly, in- regulation of gluconeogenesis by repressing forkhead box protein O1 troduction of human PXR gene to male PXR−/− mice also led to resis- (FoxO1) activity. FoxO1 is a member of the “forkhead” family of tran- tance to diet-induced obesity [53]. Therefore, the mouse PXR gene scription factors that play critical roles in gluconeogenesis in the liver promoted obesity but human PXR gene inhibited obesity in male [42]. FoxO1 promotes hepatic gluconeogenesis in liver in the fasted mice. Despite of decreased obesity, both male PXR−/− and PXR- state by activating gluconeogenic genes, including phosphoenolpyr- humanized mice had increased fasting glucose levels and severely im- uvate carboxykinase 1 (PEPCK1), glucose-6-phosphatase (G-6-P) and paired glucose tolerance which were coincident with impaired induc- insulin-like growth factor-binding protein 1. Kodama et al. [41] identi- tion of glucokinase involved in glucose utilization in liver [53].The fied FoxO1 as a co-activator for PXR. However, PXR acts as a co- increased insulin-resistant phenotype of male PXR−/− mice repressor of FoxO1 and inhibits FoxO1-mediated transcription by contradicted to what He et al. demonstrated in their study [39].Never- preventing its binding to its response elements in target genes such as theless, the authors concluded that the impact of PXR on HFD-induced PEPCK1 and G-6-P [41]. Further studies revealed that activation of PXR obesity and hyperglycemia is species-dependent in male mice. Spruiell can also repress transcription of PEPCK1 and G-6-P by inhibiting hepa- and colleagues then conducted a similar study in pre-menopausal fe- tocyte nuclear factor 4α (HNF4α) and cAMP response element- male mice [54]. They found that female PXR-humanized mice also had binding protein (CREB) activity, respectively [43,44]. These studies sug- hyperinsulinemia and impaired glucose tolerance when fed an HFD gest that PXR can regulate gluconeogenesis through multiple mecha- [54]. Unlike male mice, female PXR-humanized mice were more suscep- nisms. In addition to FoxO1, Nakamura et al. [45] later reported that tible to diet-induced obesity [54]. Under basal condition, female PXR- PXR can also crosstalk with another member of the “forkhead” family, humanized had increased protein levels of hepatic CYP3A11. The key FoxA2 to mediate drug-induced repression of lipid metabolism in gluconeogenic enzymes including PEPCK1 and G-6-P were constitutive- fasting mouse livers. FoxA2 regulates ketogenesis and β-oxidation by ly activated in female PXR-humanized mice [54]. Compared with WT upregulating transcription of genes including mitochondrial 3- mice, female PXR-humanized mice also had reduced ERα but enhanced hydroxy-3-methylglutartate-CoA synthase 2 (HMGCS2) and carnitine UCP1 protein levels in WAT when fed a control diet [54]. While HFD in- palmitoyltransferase 1 A (CPT1A) during fasting or after prolonged ex- duced UCP1 expression in WAT and glucokinase protein expression in ercise [46]. Similar to the crosstalk with FoxO1, PXR can directly interact liver of WT mice, these enzymes were not affected by HFD in female with FoxA2 and repress FoxA2-mediated expression of HMGCS2 and PXR-humanized mice [54]. Further, serum 17β-estradiol levels and CPT1A. Thus, the crosstalk between PXR and FoxO1 and FoxA2 indicates ERα expression in WAT were decreased by HFD in female WT mice an important role of PXR in mediating hepatic glucose and energy but were unaffected by HFD in female PXR-humanized mice [54].Col- homeostasis. lectively, these studies demonstrated an important role of PXR in obesi- Although these studies demonstrated a novel role for hepatic PXR ty and insulin resistance. However, the functions of PXR in obesity and signaling in gluconeogenesis, the function of PXR in the regulation of insulin resistance are complex and the impact of PXR on metabolic dys- obesity and whole-body insulin sensitivity was not revealed until very functions is not only species-dependent but also gender-dependent. Fu- recently. In a well-designed study, He et al. [39] revealed a critical role ture studies are needed to define detailed mechanisms through which of PXR in obesity and type 2 diabetes. By feeding WT and PXR−/− PXR modulate obesity, glucose homeostasis, and energy metabolism in mice a HFD, they found that PXR−/− mice were resistant to diet- various animal models as well as in humans. induced obesity, hepatic steatosis, and insulin resistance. While deficiency of PXR did not affect food intake, PXR−/− mice had increased ox- 3. Role of PXR in cholesterol metabolism and lipid homeostasis ygen consumption and mitochondrial beta-oxidation, but decreased hepatic lipogenesis and inflammation. Consistently, deficiency of PXR Despite enormous research efforts and advances in treatments in the improved insulin sensitivity in mice. In addition to diet-induced obesity, past few decades, atherosclerotic CVD is predicated to remain the lead- the authors also found that ablation of PXR in leptin-deficient ob/ob ing cause of death worldwide for the next two decades, with annual mice prevented genetic obesity by increasing oxygen consumption deaths due to CVD expected to reach 24 million by 2030 [55,56].Athero- and energy expenditure [39]. Further, ob/ob mice with PXR deficiency sclerosis is a complex chronic disease involving the interaction of genet- also had improved diabetic phenotype, decreased gluconeogenesis, ic and environmental factors over multiple years. Epidemiological and increased rate of glucose disposal during euglycemic clamp. The studies have revealed numerous risk factors for atherosclerosis includ- metabolic benefits of PXR deficiency were likely due to the inhibited ing factors with strong genetic components (e.g., elevated levels of c-Jun N-terminal kinase (JNK) activation and downregulation of lipin- low-density lipoproteins [LDL] or very low-density lipoproteins 1 which is a bona fide PXR target gene [39]. Consistently, treatment [VLDL]) and environmental factors such as HFD [57,58]. The most prom- with the PXR antagonist ketaconazole improved the diabetic phenotype inent risk factor for development of atherosclerosis is hypercholesterol- of HFD-fed mice. By contrast, expression of a constitutively active form emia which may be due to genetic or environmental factors. Much work of PXR (VP-PXR) in the liver of ob/ob mice exacerbated the diabetic phe- has been done in an effort to identify genetic variations contributing to notype [39]. atherosclerosis and many genes with small to modest effects have been While He et al. [39] convincingly demonstrated that PXR signaling identified to affect atherosclerosis. However, the impact of xenobiotic promotes obesity and insulin resistance in mice, another study reported exposure on CVD remains relatively unexplored. that PCN-mediated chronic activation of PXR prevented HFD-induced Recent studies have demonstrated that PXR signaling may also con- obesity and insulin resistance in a different strain of mouse model, tribute to the development of CVD. It is well-known that many clinically AKR/J mice [47]. However, the authors also found that PCN treatment relevant PXR ligands can elevate plasma lipid levels in patients and in- decreased hepatic lipid accumulation in HFD-fed AKR/J mice [47], crease their CVD risk [48,59–63]. For example, treatment with rifampi- which is not consistent with well-established role of PXR in promoting cin, a PXR ligand used in the clinic for the treatment of tuberculosis, can hepatic steatosis [5,39,48–52]. Further, the high concentration of PCN cause hyperlipidemia [59], and short-term treatment increased the ratio (50 mg/kg), the AKR/J mouse strain, and the lack of control PXR−/− of lathosterol to cholesterol, indicator of increased cholesterol synthesis mice in the study also made it difficult to interpret their results. [64]. Treatment with ritonavir, an HIV protease inhibitor and a potent Consistent with He et al.'s finding [39], Spruiell and colleagues [53] PXR activator [65], caused hyperlipidemia and was also associated also reported that deficiency of PXR protected male mice from diet- with increased risk of CVD in HIV patients [60,61,66,67]. Long-term induced obesity [53]. Male PXR−/− mice resisted to HFD-induced re- treatment with the antiepileptic drugs carbamazipine and phenobarbi- pression of peroxisome proliferator-activated receptor (PPAR)α in tal which are also PXR ligands, increased cholesterol levels in children white adipose tissue (WAT) and induction of CPT1 expression in liver, [62]. Further, a meta-analysis of seven genome-wide association studies

Please cite this article as: C. Zhou, Novel functions of PXR in cardiometabolic disease, Biochim. Biophys. Acta (2016), http://dx.doi.org/10.1016/ j.bbagrm.2016.02.015 4 C. Zhou / Biochimica et Biophysica Acta xxx (2016) xxx–xxx found that the common genetic variants in PXR are associated with increased plasma triglyceride levels but decreased plasma LDL levels plasma LDL cholesterol levels in humans [68]. in LDL receptor knockout (LDLR−/−)mice[51]. Similar treatment also Previous studies have also demonstrated an important role of PXR in caused increased plasma triglyceride levels in ApoE−/− mice but the cholesterol metabolism. In addition to xenobiotics, various endogenous plasma cholesterol and lipoprotein levels were not reported [51]. sterol metabolites have been identified to activate PXR. For example, the While the detailed mechanisms through which PXR signaling regulates secondary bile acid lithocholic acid and its 3-keto metabolite efficiently plasma lipid and lipoprotein levels remain to be determined, all of the activate PXR [69,70] and the bile acid intermediates, 5-cholestanoic evidence suggests that modulation of PXR can affect lipid metabolism acid-3,7,12-triols and 7α-hydroxy-4-cholesten-3-one and 4- and plasma lipid levels in different animal models. cholesten-3-one are also ligands for PXR [71]. These bile acid precursors have been claimed to be endogenous ligands for murine PXR but they 4. Role of PXR in mediating intestinal lipid uptake and transport do not affect human PXR activity [71,72]. Activation of PXR by these sterol compounds provides an important alternative pathway for sterol The discovery of the role of PXR in lipid homeostasis has provided a clearance by stimulating CYP3A expression, which hydroxylates the novel mechanism for drug or xenobiotic-induced dyslipidemia and side chain of sterols and bile acid intermediates [71,72].Further,activa- prompted more research to investigate the contribution of PXR to ad- tion of PXR can also repress the expression of CYP7A1, the first and rate verse effects of clinically relevant drugs on lipid homeostasis. For exam- limiting step in the metabolism of cholesterol to bile acids [69,70].Con- ple, CVD has become a major comorbidity for individuals being treated sistently, deficiency of PXR led to acute hepatorenal failure in mice for HIV with anti-retroviral (ARV) therapy and large-scale clinical stud- when fed a diet containing high cholesterol and cholic acid levels [73]. ies have concluded that ARV drugs are associated with dyslipidemia and Therefore, PXR plays an important role in the detoxification of choles- increased risk of CVD in HIV-infected patients [81–85]. Interestingly, terol metabolites in liver. Paradoxically, PXR also transcriptionally regu- several widely used ARV drugs such as ritonavir have been previously lates many hepatic lipogenic genes including CD36, stearoyl-CoA demonstrated to activate PXR [65] and recent studies have identified desaturase-1 (SCD-1), fatty acid elongase (FAE), 7-dehydrocholesterol more ARV drugs including amprenavir and nelfinavir as PXR ligands reductase, S14, lipin-1, and SLC13A5 [5,39,48–52,74,75]. Activation of [86]. These PXR agonistic ARV drugs have been associated with dyslipid- PXR can lead to hepatic steatosis in several animal models [48,51,76, emia and increased CVD risk in HIV-infected patients [82,87,88]. A re- 77]. To date, hepatic PXR signaling has been well-established to pro- cent study showed that short-term exposure to amprenavir by oral mote lipid accumulation, which may contribute to drug-induced delivery can significantly increase plasma total cholesterol and LDL cho- steatosis. lesterol levels in WT mice [86]. By contrast, amprenavir did not affect Although these studies suggest that PXR regulates cholesterol and plasma cholesterol levels in PXR−/− mice [86], demonstrating a poten- lipid homeostasis at multiple levels, only a few studies have investigat- tial role of PXR in mediating adverse effects of ARV drugs. PXR is ed the impact of PXR on whole-body lipid homeostasis and plasma lipid expressed at high levels in the liver and intestine, two organs that levels in animal models. Several early studies showed that PXR activa- play a central role in whole-body lipid homeostasis. Interestingly, tion affected serum high-density lipoprotein (HDL) cholesterol and apo- amprenavir regulated PXR target genes in the intestine but not in the lipoprotein (Apo)A-I levels [78,79]. For example, Masson et al. [79] liver, which was likely due to the low dose of amprenavir (10 mg/kg found that the inhibitory effects of bile acids on HDL and ApoA-I levels body weight/day) and short-term treatment (1 week) used in this were more pronounced in PXR-deficient mice whereas these effects study [86]. In addition to prototypic PXR target genes involved in xeno- were blocked in PXR-humanized mice [79]. Another study claimed biotic metabolism such as CYP3A11 and MDR1a, amprenavir stimulated that induction of CYP3A by some PXR ligands was positively correlated expression of several key genes involved in intestinal lipid homeostasis with induction of ApoA-I mRNA as well as plasma HDL and ApoA-I levels including CD36, diacylglycerol acyltransferase 1 and 2 (DGAT1 and 2). in mice [78]. However, they also found that the human PXR-specific li- Several other studies also suggested that PXR plays an important gand, rifampicin, which lacks the ability to activate the rodent PXR, role in the regulation of intestine lipid homeostasis. Ricketts et al. [89] gave positive results in mice [78], suggesting the involvement of a reported that cafestol, presented in unfiltered brewed coffee and the non-PXR-dependent mechanism. Moreover, de Hann et al. [80] report- most potent cholesterol-elevating compound known in the human ed that activation of PXR by PCN treatment increased plasma total diet, is an agonist of both PXR and farnesoid X receptor (FXR). Cafestol cholesterol and VLDL levels in ApoE*3-Leiden mice which exhibit a induced intestinal CYP27A1 and ABCA1 expression and promoted cho- human-like lipoprotein distribution on a cholesterol-rich diet. Contrary lesterol efflux to the liver via PXR activation [89], which was consistent to Bachmann et al.'s findings [78], PCN-mediated PXR activation de- with a previous report demonstrating similar effects in intestinal cells creased HDL cholesterol levels in ApoE*3-Leiden cholesteryl ester trans- in vitro [90]. Cheng et al. [50] also demonstrated that chronic exposure fer protein (CETP) transgenic mice [80]. Although several hepatic genes to rifaximin, a nonsystemic antibiotic that activates human PXR only in involved in HDL metabolism, including ATP-binding cassette transport- the gut [91], stimulated the expression of lipid transportation genes in- er (ABCA)1 and ApoA1 were affected by treatment of PCN at relatively cluding CD36, DGAT1 and DGAT2 in the intestine of PXR-humanized high concentration (0.1% in diet), the detailed mechanisms through mice, leading to increased triglyceride secretion and hepatic steatosis which PXR regulates HDL metabolism remain elusive. [50]. However, altered expression of these genes cannot fully explain The systemic impacts of chronic PXR activation on plasma lipid the elevated plasma cholesterol levels elicited by either amprenavir levels were further investigated by several independent groups. Activa- [86] or rifaximin [50]. tion of PXR by feeding PCN to WT mice was found to significantly in- The link between intestinal PXR signaling and xenobiotic-induced crease plasma total cholesterol levels and VLDL and LDL cholesterol hyperlipidemia was further confirmed by a more recent study. Tributyl levels in one study [63]. By contrast, PCN had no effect on plasma lipid citrate (TBC), one of a large group of FDA-approved pharmaceutical level in PXR knockout mice (PXR−/−)mice[63], suggesting that the plasticizers, has been identified as a potent and selective PXR agonist PCN-mediated effects were through PXR signaling. Consistent with de [92,93]. Similar to rifaximin, TBC activated intestinal PXR but does not Hann et al.'s report [80], chronic PXR activation in ApoE−/− mice was affect hepatic PXR activity [92]. Nevertheless, short-term TBC exposure also found to decrease plasma HDL levels [63]. PXR activation signifi- increased plasma total cholesterol and atherogenic LDL cholesterol cantly regulated genes in the liver involved in lipoprotein transporta- levels in WT mice, but not in PXR−/− mice [92]. In addition to CD36, tion and cholesterol metabolism, including CD36, ApoA-IV, and TBC-mediated PXR activation stimulated the expression of the intestinal CYP39A1, in both WT and ApoE−/− mice [63]. Another study demon- transporter Niemann-Pick C1-Like 1 (NPC1L1), an essential transporter strated that short-term activation PXR by intraperitoneal injection of in mediating intestinal cholesterol uptake [94–96]. NPC1L1 takes up free relatively high concentration of PCN at 80 mg/kg/day for 3 days cholesterol into cells via vesicular endocytosis and is required for

Please cite this article as: C. Zhou, Novel functions of PXR in cardiometabolic disease, Biochim. Biophys. Acta (2016), http://dx.doi.org/10.1016/ j.bbagrm.2016.02.015 C. Zhou / Biochimica et Biophysica Acta xxx (2016) xxx–xxx 5 intestinal cholesterol absorption [94,95,97]. Indeed, TBC promoted Collectively, these studies demonstrated that intestinal PXR plays a cholesterol uptake by both murine and human intestinal cells in a dual role in xenobiotic metabolism and lipid homeostasis (Fig. 1). In ad- PXR-dependent manner [92]. Inactivating mutations in NPC1L1 has re- dition to promoting xenobiotic metabolism and excretion through reg- cently been associated with reduced plasma LDL cholesterol levels and a ulation of xenobiotic-metabolizing enzymes and transporters, PXR reduced risk of CVD in a large scale human study [98].NPC1L1isalsothe signaling also regulates key genes involved in intestinal lipid uptake molecular target of the clinically used drug ezetimibe, a potent choles- and transportation including NPC1L1, CD36, and DGATs to modulate terol absorption inhibitor widely used to treat hypercholesterolemia lipid homeostasis. Future studies are needed to define the precise mech- [95]. Interestingly, ezetimibe can effectively reduce LDL cholesterol anisms through which intestinal PXR transcriptionally regulates poten- levels in HIV-infected patients taking ARV drugs [99,100]. Despite the tial target genes such as LipA and LipF and modulates lipid homeostasis established function of NPC1L1 in intestinal cholesterol absorption, the in animal models as well as in humans. transcriptional regulation of NPC1L1 was not fully understood. A PXR- binding site in the human NPC1L1 promoter was then identified, indi- 5. Role of PXR in regulating atherosclerosis development and cating NPC1L1 is a bona fide PXR target gene [92]. Thus, PXR- vascular functions mediated NPC1L1 upregulation may contribute to TBC and other PXR ligand-induced hypercholesterolemia. In addition to liver and intestine, PXR is also expressed in immune While NPC1L1 plays an essential role in intestinal cholesterol ab- cells including T cells, B cells, and macrophages [63,108–113]. Many of sorption, another PXR-regulated transporter, CD36, mediates those cells directly contribute to atherosclerosis initiation and develop- enterocyte uptake of fatty acids, which are then converted to triglycer- ment. For example, macrophages play a critical role in atherogenesis ides for transport into chylomicrons [97,101]. Several studies have also and accumulation of lipid-loaded macrophages is a hallmark or athero- indicated that CD36 mediates cholesterol uptake in the intestine [101, sclerosis [57,58]. Several studies have indicated that PXR may directly 102] and cholesterol uptake was significantly decreased in the regulate atherosclerosis development independent of dyslipidemia. enterocytes isolated from CD36-deficient (CD36−/−) mice [102].Ina CD36 [48], a direct transcriptional target of PXR, is a key molecule that lipid infusion study, CD36−/− mice exhibited accumulation of dietary mediates macrophages lipid uptake and foam cell formation cholesterol in the intestinal lumen and reduction of cholesterol trans- [114–118]. Activation of PXR was found to increase CD36 expression port into the lymph [101]. It is plausible that the PXR-mediated CD36 and lipid accumulation in macrophages of ApoE−/− mice and chronic upregulation also contributes to xenobiotic-stimulated elevation of cho- PXR activation significantly increased atherosclerotic lesions in lesterol levels. Further, DHR96, a Drosophila PXR ortholog, has been ApoE−/− mice [63]. By contrast, PXR loss-of-function decreased athero- demonstrated to regulate the intestine lipase Magro (CG5932) which sclerosis in ApoE−/− mice without altering plasma lipid levels, in part mediates cholesterol and triglyceride homeostasis in Drosophila [103]. due to decreased CD36 expression and CD36-mediated lipid uptake in Magro protein is most similar to mammalian gastric lipase (LipF) (56% macrophages [119]. similarity) and lysosomal lipase (LipA) (50% similarity) [86,103]. LipA These studies provided novel mechanistic links explaining how ex- plays an important role in the hydrolysis of cholesterol esters and tri- posure to certain xenobiotics causes atherogenic effects without glycerides within lipoprotein particles internalized by receptor- affecting plasma lipid levels. For example, numerous studies implicate mediated endocytosis [104,105] and LipF contributes to lipid catabolism that exposure to BPA, a ubiquitous environmental chemical, may by hydrolysis of dietary triglycerides in the stomach and intestine se- cause adverse health effects in humans [120–122]. Recent large and quentially producing free fatty acids and diacylglycerol [106,107]. Inter- well-controlled cross-sectional and longitudinal studies have found estingly, activation of PXR can induce both LipA and LipF expression in that higher BPA exposure is consistently associated with an increased mouse intestine [86], but it is currently unclear whether LipA and LipF risk of CVD or atherosclerosis development [123–127]. Further, these are direct transcriptional targets of PXR. associations are independent of traditional CVD risk factors including body mass index, blood pressure, lipid concentrations, and levels of physical activity [123,125]. However, the underlying mechanisms responsible for these associations remain elusive, which continues to hamper rational assessment of the health risks of BPA exposure [120, 128]. BPA and several of its analogs have been identified as ligands of PXR [14], suggesting that BPA-mediated PXR activation could potentially accelerate atherosclerosis development and increase CVD risk in humans. Interestingly, BPA is a potent agonist for human PXR but not for mouse or rat PXR [14]. To investigate the effects of BPA exposure on atherosclerosis development, a PXR-humanized ApoE-deficient mouse model was generated [129]. Feeding study concluded that BPA increased atherosclerosis in ApoE−/− mice in a human PXR- dependent manner [129]. BPA-mediated human PXR activation also increased CD36 expression, lipid accumulation, and foam cell formation in macrophages of PXR-humanized ApoE−/− deficient mice [129]. These findings identified a potential molecular mechanism that links BPA exposure to increased risk of CVD in exposed individuals and provided evidence to inform future risk assessment for BPA as well as other relevant chemicals. Atherosclerosis has also been considered a chronic inflammatory disease [130,131]. Many inflammatory pathways that contribute to the initiation and progression of atherosclerosis are regulated by the transcription factor NF-κB, a master regulator of the innate and adaptive Fig. 1. Dual role of intestinal PXR in xenobiotic metabolism and lipid homeostasis. immune responses [132–134]. Interestingly, it has been demonstrated Activation of PXR stimulates expression of xenobiotic metabolizing enzymes and that PXR can regulate inflammation via crosstalk with NF-κBsignaling transporters to promote xenobiotic metabolism and excretion. PXR also regulates key – κ genes mediating intestinal lipid uptake and transport to induce hyperlipidemia. PXRE, pathway [134 136].NF- B signaling activation has been implicated in PXR response element. pathogenesis of atherosclerosis [131,133] and studies have

Please cite this article as: C. Zhou, Novel functions of PXR in cardiometabolic disease, Biochim. Biophys. Acta (2016), http://dx.doi.org/10.1016/ j.bbagrm.2016.02.015 6 C. Zhou / Biochimica et Biophysica Acta xxx (2016) xxx–xxx demonstrated the complex functions of NF-κB signaling in atherosclero- that PXR can be synergistically activated by a mixture of xenobiotics in- sis [137–140]. However, the crosstalk between PXR and NF-κB signaling cluding pharmaceutical and environmental chemicals [14,145,146].For has not been investigated in the concept of atherosclerosis and future examples, Sui et al. reported that BPA and analogs can synergistically studies are needed to determine whether PXR-NF-κB crosstalk can activate human PXR, and computational docking study indicated that regulate atherosclerosis development when exposure to PXR-relevant BPA and its analog may bind to PXR LBD simultaneously [14].Venkatesh xenobiotics in appropriate animal models. et al. demonstrated that indole 3-propionic acid (IPA), an indole In addition to macrophages, PXR is also expressed in vascular tissue metabolite produced in the gut, is a weak human PXR agonist but IPA [141] and vascular cells including smooth muscle cells (SMCs) and en- can robustly activate PXR in the presence of indole [146].Morerecently, dothelial cells (ECs) [142–144]. Hagedorn et al. [141] first reported it has been shown that pesticide trans-nonachlor and pharmaceutical that PXR regulates vascular tone and contributes to the development chemical 17α-ethinylestradiol can also produce synergistic effects on of vascular adaptations to pregnancy. They found that treatment with PXR activity [145]. A fundamental question about exposure to xenobiot- progesterone metabolite, 5β-dihydroprogesterone, led to PXR- ic chemicals including EDCs is whether low-dose exposure to those dependent increases in vasorelaxation in both nonpregnant and preg- chemicals can influence various signaling pathways and induce adverse nant mice, which was likely due to activation of cytochrome p450 effects in humans. The synergism between different PXR-agonistic epoxygenases [141]. Swales et al. [142] confirmed that PXR is expressed chemicals supports the need to include mixtures for future in vitro in primary human and rat aortic SMCs as well as human and rat aorta. and in vivo studies, which may have important implications for toxicol- Activation of PXR increased xenobiotic metabolism by stimulating ex- ogy, endocrine disruption study, and chemical risk assessment. Combi- pression of Phase 1 and II drug-metabolisms and transporters including nations of PXR-agonistic chemicals including pharmaceutical drugs and CYP3A23, GSTM1, multidrug resistance-associated protein 1 (MRP1) in environmental chemicals may produce significant effects on PXR activ- vascular cells, leading to decreased oxidative stress in those cells [142]. ity and cardiometabolic disease in humans, even when each chemical is PXR therefore may protect the vasculature from oxidative stress elicited present at low doses that individually do not induce observable effects. by endogenous and exogenous insults. More recently, Wang et al. [143] There are now more than 100,000 man-made chemicals on the market showed that the atheroprotective flow, laminar shear stress, activated and only a relatively small subset of chemicals have been identified to PXR, and induced expression of PXR-regulated genes encoding phase I have potential adverse effects such as endocrine disrupting activities and II metabolizing enzyme and transporters. By contrast, the [147]. Considering PXR's extraordinary ligand-binding properties in- atheroprone flow, oscillatory shear stress, suppressed PXR. Laminar cluding the ability to be activated by mixtures, it is important to identify shear stress-mediated PXR activation protected ECs from apoptosis trig- more xenobiotics as PXR ligand and to further characterize its role in gered by doxorubicin via the induction of detoxification genes including cardiometabolic disease. Such studies will not only significantly contrib- CYP1B1, GSTM4, and MDR1. Consistent with previous reports [134,135], ute to our understanding of “gene–environment interactions” in predis- activation of PXR also suppressed the NF-κB activity and inhibit TNFα or posing individuals to chronic diseases but also provide a novel LPS-induced expression of proinflammatory adhesion molecules such therapeutic target to combat these diseases. as vascular cell adhesion molecule-1 and E-selectin in ECs and in rat carotid arteries [143]. These results suggest that PXR signaling may pro- Conflict of interest tect SMCs, ECs, and vasculature against potential harmful effects induced by endobiotics or environmental xenobiotics. Interestingly, The author, Changcheng Zhou, declares no conflict of interest. Wang et al. [144] also found that PXR can regulate innate immunity by activating NLRP3 inflammasome in cultured ECs in another study. Acknowledgments PXR can transcriptionally regulate NLRP3 expression and activation of PXR triggered the activation of NLRP3 inflammasome, leading to the We apologize to all the authors whose work could not be cited be- cleavage and maturation of caspase-1 and IL-1β in ECs [144]. Therefore, cause of space restrictions. This work was supported by NIH grants PXR signaling can potentially have both pro-atherogenic and anti- (R01ES023470, R01HL123358, and R21ES022745) to C.Z. atherogenic effects in different vascular cells. The precise mechanisms through which PXR modulates vascular functions and atherosclerosis, in animal models and in humans, remain to be determined. References

[1] B. Blumberg, W. Sabbagh Jr., H. Juguilon, J. Bolado Jr., C.M. van Meter, E.S. Ong, R.M. 6. Conclusion Evans, SXR, a novel steroid and xenobiotic-sensing nuclear receptor, Genes Dev. 12 (1998) 3195–3205. Influences of the chemical environment on human health have re- [2] S.A. Kliewer, J.T. Moore, L. Wade, J.L. Staudinger, M.A. Watson, S.A. Jones, D.D. McKee, B.B. Oliver, T.M. Willson, R.H. Zetterstrom, T. Perlmann, J.M. Lehmann, An cently become the subject of intense interest. PXR was originally identi- orphan nuclear receptor activated by pregnanes defines a novel steroid signaling fied as a xenobiotic sensor that regulates the metabolism and excretion pathway, Cell 92 (1998) 73–82. of a large variety of endobiotic, dietary, and xenobiotic chemicals. The [3] G. Bertilsson, J. Heidrich, K. Svensson, M. Asman, L. Jendeberg, M. Sydow-Backman, R. Ohlsson, H. Postlind, P. Blomquist, A. Berkenstam, Identification of a human extraordinary chemical diversity of PXR ligands and the marked nuclear receptor defines a new signaling pathway for CYP3A induction, Proc. species-specific differences in the pharmacological activation profiles Natl. Acad. Sci. U. S. A. 95 (1998) 12208–12213. of PXR have led many laboratories to study the impact of numerous xe- [4] S.A. Kliewer, B. Goodwin, T.M. Willson, The nuclear pregnane X receptor: a key regulator of xenobiotic metabolism, Endocr. Rev. 23 (2002) 687–702. nobiotics, including clinically used drugs and known and suspected [5] C. Zhou, S. Verma, B. Blumberg, The steroid and xenobiotic receptor (SXR), beyond EDCs, on activation of PXR [5]. The discovery of novel and unsuspected xenobiotic metabolism, Nucl. Recept. Signal. 7 (2009), e001. roles for PXR in obesity, insulin resistance, lipid homeostasis, atherogen- [6] B. Blumberg, R.M. Evans, Orphan nuclear receptors–new ligands and new possibil- – esis, and vascular functions suggests that PXR signaling may contribute ities, Genes Dev. 12 (1998) 3149 3155. [7] F.P. Guengerich, Cytochrome P-450 3 A4: regulation and role in drug metabolism, significantly to the pathophysiological effects of many known xenobi- Annu. Rev. Pharmacol. Toxicol. 39 (1999) 1–17. otics on cardiometabolic disease in humans. However, the functions of [8] M. Baes, T. Gulick, H.S. Choi, M.G. Martinoli, D. Simha, D.D. Moore, A new orphan member of the nuclear hormone receptor superfamily that interacts with a subset PXR in cardiometabolic disease are complex and future studies are – fi fi of retinoic acid response elements, Mol. Cell. Biol. 14 (1994) 1544 1552. needed to de ne the cell/tissue-speci c role of PXR in cardiometabolic [9] B.M. Forman, I. Tzameli, H.S. Choi, J. Chen, D. Simha, W. Seol, R.M. Evans, D.D. disease in a clinically relevant environment. In addition to cardiometa- Moore, Androstane metabolites bind to and deactivate the nuclear receptor CAR- bolic disease, PXR has a number of other important functions in the beta, Nature 395 (1998) 612–615. fl fl [10] P. Wei, J. Zhang, M. Egan-Ha ey, S. Liang, D.D. Moore, The nuclear receptor CAR body including in ammation, bone homeostasis, and tumorigenesis mediates specific xenobiotic induction of drug metabolism, Nature 407 (2000) that remain to be fully explored. Further, recent studies also revealed 920–923.

[11] W. Xie, R.M. Evans, Orphan nuclear receptors: the exotics of xenobiotics, J. Biol. [42] M. Montminy, S.H. Koo, Diabetes: outfoxing insulin resistance? Nature 432 (2004) Chem. 276 (2001) 37739–37742. 958–959. [12] S.A. Jones, L.B. Moore, J.L. Shenk, G.B. Wisely, G.A. Hamilton, D.D. McKee, N.C. [43] S. Bhalla, C. Ozalp, S. Fang, L. Xiang, J.K. Kemper, Ligand-activated pregnane X re- Tomkinson, E.L. LeCluyse, M.H. Lambert, T.M. Willson, S.A. Kliewer, J.T. Moore, ceptor interferes with HNF-4 signaling by targeting a common coactivator PGC- The pregnane X receptor: a promiscuous xenobiotic receptor that has diverged 1alpha. functional implications in hepatic cholesterol and glucose metabolism, J. during evolution, Mol. Endocrinol. 14 (2000) 27–39. Biol. Chem. 279 (2004) 45139–45147. [13] E.L. LeCluyse, Pregnane X receptor: molecular basis for species differences in [44] S. Kodama, R. Moore, Y. Yamamoto, M. Negishi, Human nuclear pregnane X recep- CYP3A induction by xenobiotics, Chem. Biol. Interact. 134 (2001) 283–289. tor cross-talk with CREB to repress cAMP activation of the glucose-6-phosphatase [14] Y. Sui, N. Ai, S.H. Park, J. Rios-Pilier, J.T. Perkins, W.J. Welsh, C. Zhou, Bisphenol a and gene, Biochem. J. 407 (2007) 373–381. its analogues activate human pregnane x receptor, Environ. Health Perspect. 120 [45] K. Nakamura, R. Moore, M. Negishi, T. Sueyoshi, Nuclear pregnane X receptor (2012) 399–405. cross-talk with FoxA2 to mediate drug-induced regulation of lipid metabolism in [15] H. Masuyama, Y. Hiramatsu, M. Kunitomi, T. Kudo, P.N. MacDonald, Endocrine fasting mouse liver, J. Biol. Chem. 282 (2007) 9768–9776. disrupting chemicals, phthalic acid and nonylphenol, activate pregnane X [46] C. Wolfrum, E. Asilmaz, E. Luca, J.M. Friedman, M. Stoffel, Foxa2 regulates lipid me- receptor-mediated transcription, Mol. Endocrinol. 14 (2000) 421–428. tabolism and ketogenesis in the liver during fasting and in diabetes, Nature 432 [16] A.Takeshita,N.Koibuchi,J.Oka,M.Taguchi,Y.Shishiba,Y.Ozawa,Bisphenol-A,anen- (2004) 1027–1032. vironmental estrogen, activates the humanorphannuclearreceptor,steroidandxe- [47] Y. Ma, D. Liu, Activation of pregnane X receptor by pregnenolone 16 alpha- nobiotic receptor-mediated transcription, Eur. J. Endocrinol. 145 (2001) 513–517. carbonitrile prevents high-fat diet-induced obesity in AKR/J mice, PLoS One 7 [17] C. Zhou, M.M. Tabb, A. Sadatrafiei, F. Grun, B. Blumberg, Tocotrienols activate the (2012), e38734. steroid and xenobiotic receptor, SXR, and selectively regulate expression of its tar- [48] J. Zhou, Y. Zhai, Y. Mu, H. Gong, H. Uppal, D. Toma, S. Ren, R.M. Evans, W. Xie, A get genes, Drug Metab. Dispos. 32 (2004) 1075–1082. novel pregnane X receptor-mediated and sterol regulatory element-binding [18] J. Cheng, Y.M. Shah, X. Ma, X. Pang, T. Tanaka, T. Kodama, K.W. Krausz, F.J. Gonzalez, protein-independent lipogenic pathway, J. Biol. Chem. 281 (2006) 15013–15020. Therapeutic role of rifaximin in inflammatory bowel disease: clinical implication of [49] W. de Haan, J. de Vries-van der Weij, I.M. Mol, M. Hoekstra, A.R. J., J.W. Jukema, L.M. human pregnane X receptor activation, J. Pharmacol. Exp. Ther. 335 (2010) 32–41. Havekes, H.M. Princen, P.C. Rensen, PXR agonism decreases plasma HDL levels in [19] D.P. Hartley, X. Dai, Y.D. He, E.J. Carlini, B. Wang, S.E. Huskey, R.G. Ulrich, T.H. ApoE3-Leiden.CETP mice, Biochim Biophys Acta 1791 (2009) 191–197. Rushmore, R. Evers, D.C. Evans, Activators of the rat pregnane X receptor differen- [50] J. Cheng, K.W. Krausz, N. Tanaka, F.J. Gonzalez, Chronic exposure to rifaximin tially modulate hepatic and intestinal gene expression, Mol. Pharmacol. 65 (2004) causes hepatic steatosis in pregnane x receptor-humanized mice, Toxicol. Sci. 1159–1171. 129 (2012) 456–468. [20] Y.C. Wang, K. McPherson, T. Marsh, S.L. Gortmaker, M. Brown, Health and econom- [51] M. Hoekstra, B. Lammers, R. Out, Z. Li, M. Van Eck, T.J. Van Berkel, Activation of the ic burden of the projected obesity trends in the USA and the UK, Lancet 378 (2011) nuclear receptor PXR decreases plasma LDL-cholesterol levels and induces hepatic 815–825. steatosis in LDL receptor knockout mice, Mol. Pharm. 6 (2009) 182–189. [21] M.F. Gregor, G.S. Hotamisligil, Inflammatory mechanisms in obesity, Annu. Rev. [52] A.Moreau,C.Teruel,M.Beylot,V.Albalea,V.Tamasi,T.Umbdenstock,Y.Parmentier, Immunol. 29 (2011) 415–445. A.Sa-Cunha,B.Suc,J.M.Fabre,F.Navarro,J.Ramos,U.Meyer,P.Maurel,M.J.Vilarem, [22] L.F. Van Gaal, I.L. Mertens, C.E. De Block, Mechanisms linking obesity with cardio- J.M. Pascussi, A novel pregnane X receptor and S14-mediated lipogenic pathway in vascular disease, Nature 444 (2006) 875–880. human hepatocyte, Hepatology 49 (2009) 2068–2079. [23] F.S. Vom Saal, J.P. Myers, Bisphenol a and risk of metabolic disorders, JAMA 300 [53] K. Spruiell, R.M. Richardson, J.M. Cullen, E.M. Awumey, F.J. Gonzalez, M.A. Gyamfi, (2008) 1353–1355. Role of pregnane X receptor in obesity and glucose homeostasis in male mice, J. [24] C. Casals-Casas, B. Desvergne, Endocrine disruptors: from endocrine to metabolic Biol. Chem. 289 (2014) 3244–3261. disruption, Annu. Rev. Physiol. 73 (2011) 135–162. [54] K. Spruiell, D.Z. Jones, J.M. Cullen, E.M. Awumey, F.J. Gonzalez, M.A. Gyamfi,Roleof [25] J.L. Carwile, K.B. Michels, Urinary bisphenol A and obesity: NHANES 2003-2006, human pregnane X receptor in high fat diet-induced obesity in pre-menopausal fe- Environ. Res. 111 (2011) 825–830. male mice, Biochem. Pharmacol. 89 (2014) 399–412. [26] E. Diamanti-Kandarakis, J.P. Bourguignon, L.C. Giudice, R. Hauser, G.S. Prins, A.M. [55] P.A. Heidenreich, J.G. Trogdon, O.A. Khavjou, J. Butler, K. Dracup, M.D. Ezekowitz, Soto, R.T. Zoeller, A.C. Gore, Endocrine-disrupting chemicals: an Endocrine Society E.A. Finkelstein, Y. Hong, S.C. Johnston, A. Khera, D.M. Lloyd-Jones, S.A. Nelson, G. scientific statement, Endocr. Rev. 30 (2009) 293–342. Nichol, D. Orenstein, P.W. Wilson, Y.J. Woo, Forecasting the future of cardiovascular [27] R.R. Newbold, E. Padilla-Banks, R.J. Snyder, T.M. Phillips, W.N. Jefferson, Develop- disease in the United States: a policy statement from the American Heart Associa- mental exposure to endocrine disruptors and the obesity epidemic, Reprod. tion, Circulation 123 (2011) 933–944. Toxicol. 23 (2007) 290–296. [56] D. Lloyd- Jones, R.J. Adams, T.M. Brown, M. Carnethon, S. Dai, G. De Simone, T.B. [28] F. Grun, H. Watanabe, Z. Zamanian, L. Maeda, K. Arima, R. Cubacha, D.M. Gardiner, J. Ferguson, E. Ford, K. Furie, C. Gillespie, A. Go, K. Greenlund, N. Haase, S. Hailpern, Kanno, T. Iguchi, B. Blumberg, Endocrine-disrupting organotin compounds are po- P.M. Ho, V. Howard, B. Kissela, S. Kittner, D. Lackland, L. Lisabeth, A. Marelli, M.M. tent inducers of adipogenesis in vertebrates, Mol. Endocrinol. 20 (2006) McDermott, J. Meigs, D. Mozaffarian, M. Mussolino, G. Nichol, V.L. Roger, W. 2141–2155. Rosamond, R. Sacco, P. Sorlie, R. Stafford, T. Thom, S. Wasserthiel-Smoller, N.D. [29] F. Grun, B. Blumberg, Perturbed nuclear receptor signaling by environmental Wong, J. Wylie-Rosett, Executive summary: heart disease and stroke statistics– obesogens as emerging factors in the obesity crisis, Rev. Endocr. Metab. Disord. 8 2010 update: a report from the American Heart Association, Circulation 121 (2007) 161–171. (2010) 948–954. [30] T.T. Schug, A. Janesick, B. Blumberg, J.J. Heindel, Endocrine disrupting chemicals [57] A.J. Lusis, Atherosclerosis, Nature 407 (2000) 233–241. and disease susceptibility, J. Steroid Biochem. Mol. Biol. (2011). [58] C.K. Glass, J.L. Witztum, Atherosclerosis. The road ahead, Cell 104 (2001) 503–516. [31] R.J. Kavlock, G.P. Daston, C. DeRosa, P. Fenner-Crisp, L.E. Gray, S. Kaattari, G. Lucier, [59] A.M. Khogali, B.I. Chazan, V.J. Metcalf, J.H. Ramsay, Hyperlipidaemia as a complica- M. Luster, M.J. Mac, C. Maczka, R. Miller, J. Moore, R. Rolland, G. Scott, D.M. tion of rifampicin treatment, Tubercle 55 (1974) 231–233. Sheehan, T. Sinks, H.A. Tilson, Research needs for the risk assessment of health [60] A. Carr, K. Samaras, D.J. Chisholm, D.A. Cooper, Pathogenesis of HIV-1-protease and environmental effects of endocrine disruptors: a report of the U.S. EPA- inhibitor-associated peripheral lipodystrophy, hyperlipidaemia, and insulin sponsored workshop, Environ. Health Perspect. 104 (Suppl. 4) (1996) 715–740. resistance, Lancet 351 (1998) 1881–1883. [32] T. Colborn, D. Dumanoski, J.P. Meyers, Our Stolen Future, 1996. [61] S.D. Shafran, L.D. Mashinter, S.E. Roberts, The effect of low-dose ritonavir mono- [33] L. Gross, The toxic origins of disease, PLoS Biol. 5 (2007), e193. therapy on fasting serum lipid concentrations, HIV Med. 6 (2005) 421–425. [34] M.M. Tabb, V. Kholodovych, F. Grun, C. Zhou, W.J. Welsh, B. Blumberg, Highly chlo- [62] J.M. Eiris, S. Lojo, M.C. Del Rio, I. Novo, M. Bravo, P. Pavon, M. Castro-Gago, Effects of rinated PCBs inhibit the human xenobiotic response mediated by the steroid and long-term treatment with antiepileptic drugs on serum lipid levels in children xenobiotic receptor (SXR), Environ. Health Perspect. 112 (2004) 163–169. with epilepsy, Neurology 45 (1995) 1155–1157. [35] J.G. DeKeyser, E.M. Laurenzana, E.C. Peterson, T. Chen, C.J. Omiecinski, Selective [63] C. Zhou, N. King, K.Y. Chen, J.L. Breslow, Activation of PXR induces hypercholester- phthalate activation of naturally occurring human constitutive androstane recep- olemia in wild-type and accelerates atherosclerosis in apoE deficient mice, J. Lipid tor splice variants and the pregnane X receptor, Toxicol. Sci. 120 (2011) 381–391. Res. 50 (2009) 2004–2013. [36] N. Takasu, T. Yamada, H. Miura, S. Sakamoto, M. Korenaga, K. Nakajima, M. [64] D. Lutjohann, C. Hahn, W. Prange, T. Sudhop, M. Axelson, T. Sauerbruch, K. von Kanayama, Rifampicin-induced early phase hyperglycemia in humans, Am. Rev. Bergmann, C. Reichel, Influence of rifampin on serum markers of cholesterol and Respir. Dis. 125 (1982) 23–27. bile acid synthesis in men, Int. J. Clin. Pharmacol. Ther. 42 (2004) 307–313. [37] B.H. Peters, N.A. Samaan, Hyperglycemia with relative hypoinsulinemia in diphe- [65] I. Dussault, M. Lin, K. Hollister, E.H. Wang, T.W. Synold, B.M. Forman, Peptide nylhydantoin toxicity, N. Engl. J. Med. 281 (1969) 91–92. mimetic HIV protease inhibitors are ligands for the orphan receptor SXR, J. Biol. [38] A. Suvannasankha, C. Fausel, B.E. Juliar, C.T. Yiannoutsos, W.B. Fisher, R.H. Ansari, Chem. 276 (2001) 33309–33312. L.L. Wood, G.G. Smith, L.D. Cripe, R. Abonour, Final report of toxicity and efficacy [66] A. Carr, K. Samaras, S. Burton, M. Law, J. Freund, D.J. Chisholm, D.A. Cooper, A of a phase II study of oral cyclophosphamide, thalidomide, and prednisone for pa- syndrome of peripheral lipodystrophy, hyperlipidaemia and insulin resistance in tients with relapsed or refractory multiple myeloma: a Hoosier Oncology Group patients receiving HIV protease inhibitors, AIDS 12 (1998) F51–F58. trial,HEM01-21,Oncologist12(2007)99–106. [67] G. Barbaro, Metabolic and cardiovascular complications of highly active antiretro- [39] J. He, J. Gao, M. Xu, S. Ren, M. Stefanovic-Racic, R.M. O'Doherty, W. Xie, PXR ablation viral therapy for HIV infection, Curr. HIV Res. 4 (2006) 79–85. alleviates diet-induced and genetic obesity and insulin resistance in mice, Diabetes [68] Y. Lu, E.J. Feskens, J.M. Boer, M. Muller, The potential influence of genetic variants 62 (2013) 1876–1887. in genes along bile acid and bile metabolic pathway on blood cholesterol levels [40] J.T. Lahtela, A.J. Arranto, E.A. Sotaniemi, Enzyme inducers improve insulin sensitiv- in the population, Atherosclerosis 210 (2010) 14–27. ity in non-insulin-dependent diabetic subjects, Diabetes 34 (1985) 911–916. [69] J.L. Staudinger, B. Goodwin, S.A. Jones, D. Hawkins-Brown, K.I. MacKenzie, A. [41] S. Kodama, C. Koike, M. Negishi, Y. Yamamoto, Nuclear receptors CAR and PXR LaTour, Y. Liu, C.D. Klaassen, K.K. Brown, J. Reinhard, T.M. Willson, B.H. Koller, cross talk with FOXO1 to regulate genes that encode drug-metabolizing and S.A. Kliewer, The nuclear receptor PXR is a lithocholic acid sensor that protects gluconeogenic enzymes, Mol. Cell. Biol. 24 (2004) 7931–7940. against liver toxicity, Proc. Natl. Acad. Sci. U. S. A. 98 (2001) 3369–3374.

Please cite this article as: C. Zhou, Novel functions of PXR in cardiometabolic disease, Biochim. Biophys. Acta (2016), http://dx.doi.org/10.1016/ j.bbagrm.2016.02.015 8 C. Zhou / Biochimica et Biophysica Acta xxx (2016) xxx–xxx

[70] W. Xie, A. Radominska-Pandya, Y. Shi, C.M. Simon, M.C. Nelson, E.S. Ong, D.J. modulator of whole-body cholesterol homeostasis, J. Biol. Chem. 279 (2004) Waxman, R.M. Evans, An essential role for nuclear receptors SXR/PXR in detoxifi- 33586–33592. cation of cholestatic bile acids, Proc. Natl. Acad. Sci. U. S. A. 98 (2001) 3375–3380. [95] S.W. Altmann, H.R. Davis Jr., L.J. Zhu, X. Yao, L.M. Hoos, G. Tetzloff, S.P. Iyer, M. [71] I. Dussault, H.D. Yoo, M. Lin, E. Wang, M. Fan, A.K. Batta, G. Salen, S.K. Erickson, B.M. Maguire, A. Golovko, M. Zeng, L. Wang, N. Murgolo, M.P. Graziano, Niemann-pick Forman, Identification of an endogenous ligand that activates pregnane X C1 like 1 protein is critical for intestinal cholesterol absorption, Science 303 receptor-mediated sterol clearance, Proc. Natl. Acad. Sci. U. S. A. 100 (2003) (2004) 1201–1204. 833–838. [96] L. Jia, J.L. Betters, L. Yu, Niemann-pick C1-like 1 (NPC1L1) protein in intestinal and [72] B. Goodwin, K.C. Gauthier, M. Umetani, M.A. Watson, M.I. Lochansky, J.L. Collins, E. hepatic cholesterol transport, Annu. Rev. Physiol. 73 (2011) 239–259. Leitersdorf, D.J. Mangelsdorf, S.A. Kliewer, J.J. Repa, Identification of bile acid pre- [97] N.A. Abumrad, N.O. Davidson, Role of the gut in lipid homeostasis, Physiol. Rev. 92 cursors as endogenous ligands for the nuclear xenobiotic pregnane X receptor, (2012) 1061–1085. Proc. Natl. Acad. Sci. U. S. A. 100 (2003) 223–228. [98] I. Myocardial Infarction Genetics Consortium, N.O. Stitziel, H.H. Won, A.C. Morrison, [73] J. Sonoda, L.W. Chong, M. Downes, G.D. Barish, S. Coulter, C. Liddle, C.H. Lee, R.M. G.M. Peloso, R. Do, L.A. Lange, P. Fontanillas, N. Gupta, S. Duga, A. Goel, M. Farrall, D. Evans, Pregnane X receptor prevents hepatorenal toxicity from cholesterol metab- Saleheen, P. Ferrario, I. Konig, R. Asselta, P.A. Merlini, N. Marziliano, M.F. olites, Proc. Natl. Acad. Sci. U. S. A. 102 (2005) 2198–2203. Notarangelo, U. Schick, P. Auer, T.L. Assimes, M. Reilly, R. Wilensky, D.J. Rader, [74] J. Zhang, Y. Wei, B. Hu, M. Huang, W. Xie, Y. Zhai, Activation of human stearoyl- G.K. Hovingh, T. Meitinger, T. Kessler, A. Kastrati, K.L. Laugwitz, D. Siscovick, J.I. coenzyme A desaturase 1 contributes to the lipogenic effect of PXR in HepG2 Rotter, S.L. Hazen, R. Tracy, S. Cresci, J. Spertus, R. Jackson, S.M. Schwartz, P. cells, PLoS One 8 (2013), e67959. Natarajan, J. Crosby, D. Muzny, C. Ballantyne, S.S. Rich, C.J. O'Donnell, G. Abecasis, [75] L. Li, H. Li, B. Garzel, H. Yang, T. Sueyoshi, Q. Li, Y. Shu, J. Zhang, B. Hu, S. Heyward, T. S. Sunyaev, D.A. Nickerson, J.E. Buring, P.M. Ridker, D.I. Chasman, E. Austin, Z. Ye, Moeller, W. Xie, M. Negishi, H. Wang, SLC13A5 is a novel transcriptional target of I.J. Kullo, P.E. Weeke, C.M. Shaffer, L.A. Bastarache, J.C. Denny, D.M. Roden, C. the pregnane X receptor and sensitizes drug-induced steatosis in human liver, Palmer, P. Deloukas, D.Y. Lin, Z.Z. Tang, J. Erdmann, H. Schunkert, J. Danesh, J. Mol. Pharmacol. 87 (2015) 674–682. Marrugat, R. Elosua, D. Ardissino, R. McPherson, H. Watkins, A.P. Reiner, J.G. [76] N. Mitro, L. Vargas, R. Romeo, A. Koder, E. Saez, T0901317 is a potent PXR ligand: Wilson, D. Altshuler, R.A. Gibbs, E.S. Lander, E. Boerwinkle, S. Gabriel, S. implications for the biology ascribed to LXR, FEBS Lett. 581 (2007) 1721–1726. Kathiresan, Inactivating mutations in NPC1L1 and protection from coronary heart [77] J. Zhou, M. Febbraio, T. Wada, Y. Zhai, R. Kuruba, J. He, J.H. Lee, S. Khadem, S. Ren, S. disease, N. Engl. J. Med. 371 (2014) 2072–2082. Li, R.L. Silverstein, W. Xie, Hepatic fatty acid transporter Cd36 is a common target of [99] D.A. Wohl, D. Waters, R.J. Simpson Jr., S. Richard, A. Schnell, S. Napravnik, J. Keys, J.J. LXR, PXR, and PPARgamma in promoting steatosis, Gastroenterology 134 (2008) Eron Jr., P. Hsue, Ezetimibe alone reduces low-density lipoprotein cholesterol in 556–567. HIV-infected patients receiving combination antiretroviral therapy, Clin. Infect. [78] K. Bachmann, H. Patel, Z. Batayneh, J. Slama, D. White, J. Posey, S. Ekins, D. Gold, L. dis. 47 (2008) 1105–1108. Sambucetti, PXR and the regulation of apoA1 and HDL-cholesterol in rodents, [100] D. Chow, H. Chen, M.J. Glesby, A. Busti, S. Souza, J. Andersen, S. Kohrs, J. Wu, S.L. Pharmacol. Res. 50 (2004) 237–246. Koletar, Short-term ezetimibe is well tolerated and effective in combination with [79] D. Masson, L. Lagrost, A. Athias, P. Gambert, C. Brimer-Cline, L. Lan, J.D. Schuetz, E.G. statin therapy to treat elevated LDL cholesterol in HIV-infected patients, AIDS 23 Schuetz, M. Assem, Expression of the pregnane X receptor in mice antagonizes the (2009) 2133–2141. cholic acid-mediated changes in plasma lipoprotein profile, Arterioscler. Thromb. [101] A.M. Nauli, F. Nassir, S. Zheng, Q. Yang, C.M. Lo, S.B. Vonlehmden, D. Lee, R.J. Vasc. Biol. 25 (2005) 2164–2169. Jandacek, N.A. Abumrad, P. Tso, CD36 is important for chylomicron formation [80] W. de Haan, J. de Vries-van der Weij, I.M. Mol, M. Hoekstra, J.A. Romijn, J.W. and secretion and may mediate cholesterol uptake in the proximal intestine, Jukema, L.M. Havekes, H.M. Princen, P.C. Rensen, PXR agonism decreases plasma Gastroenterology 131 (2006) 1197–1207. HDL levels in ApoE3-leiden.CETP mice, Biochim. Biophys. Acta 1791 (2009) [102] F. Nassir, B. Wilson, X. Han, R.W. Gross, N.A. Abumrad, CD36 is important for fatty 191–197. acid and cholesterol uptake by the proximal but not distal intestine, J. Biol. Chem. [81] N. Friis-Moller, C.A. Sabin, R. Weber, A. d'Arminio Monforte, W.M. El-Sadr, P. Reiss, 282 (2007) 19493–19501. R. Thiebaut, L. Morfeldt, S. De Wit, C. Pradier, G. Calvo, M.G. Law, O. Kirk, A.N. [103] M.H. Sieber, C.S. Thummel, Coordination of triacylglycerol and cholesterol homeo- Phillips, J.D. Lundgren, Combination antiretroviral therapy and the risk of myocar- stasis by DHR96 and the drosophila LipA homolog magro, Cell Metab. 15 (2012) dial infarction, N. Engl. J. Med. 349 (2003) 1993–2003. 122–127. [82] N. Friis-Moller, P. Reiss, C.A. Sabin, R. Weber, A. Monforte, W. El-Sadr, R. Thiebaut, S. [104] R.A. Anderson, G.N. Sando, Cloning and expression of cDNA encoding human De Wit, O. Kirk, E. Fontas, M.G. Law, A. Phillips, J.D. Lundgren, Class of antiretroviral lysosomal acid lipase/cholesteryl ester hydrolase. similarities to gastric and lingual drugs and the risk of myocardial infarction, N. Engl. J. Med. 356 (2007) 1723–1735. lipases, J Biol Chem 266 (1991) 22479–22484. [83] D. Periard, A. Telenti, P. Sudre, J.J. Cheseaux, P. Halfon, M.J. Reymond, S.M. [105] S. Sheriff, H. Du, G.A. Grabowski, Characterization of lysosomal acid lipase by site- Marcovina, M.P. Glauser, P. Nicod, R. Darioli, V. Mooser, S.H.C. Study, Atherogenic directed mutagenesis and heterologous expression, J. Biol. Chem. 270 (1995) dyslipidemia in HIV-infected individuals treated with protease inhibitors, 27766–27772. Circulation 100 (1999) 700–705. [106] F. Carriere, J.A. Barrowman, R. Verger, R. Laugier, Secretion and contribution to [84] S. Lang, M. Mary-Krause, L. Cotte, J. Gilquin, M. Partisani, A. Simon, F. Boccara, D. lipolysis of gastric and pancreatic lipases during a test meal in humans, Gastroen- Costagliola, Impact of individual antiretroviral drugs on the risk of myocardial in- terology 105 (1993) 876–888. farction in human immunodeficiency virus-infected patients: a case–control [107] Y. Gargouri, G. Pieroni, C. Riviere, P.A. Lowe, J.F. Sauniere, L. Sarda, R. Verger, Impor- study nested within the French Hospital database on HIV ANRS cohort CO4, tance of human gastric lipase for intestinal lipolysis: an in vitro study, Biochim. Arch. Intern. Med. 170 (2010) 1228–1238. Biophys. Acta 879 (1986) 419–423. [85] J.H. Stein, M.A. Klein, J.L. Bellehumeur, P.E. McBride, D.A. Wiebe, J.D. Otvos, J.M. [108] S. Dubrac, A. Elentner, S. Ebner, J. Horejs-Hoeck, M. Schmuth, Modulation of T lym- Sosman, Use of human immunodeficiency virus-1 protease inhibitors is associated phocyte function by the pregnane X receptor, J. Immunol. 184 (2010) 2949–2957. with atherogenic lipoprotein changes and endothelial dysfunction, Circulation 104 [109] N. Albermann, F.H. Schmitz-Winnenthal, K. Z'Graggen, C. Volk, M.M. Hoffmann, (2001) 257–262. W.E. Haefeli, J. Weiss, Expression of the drug transporters MDR1/ABCB1, MRP1/ [86] R.N. Helsley, Y. Sui, N. Ai, S.H. Park, W.J. Welsh, C. Zhou, Pregnane X receptor me- ABCC1, MRP2/ABCC2, BCRP/ABCG2, and PXR in peripheral blood mononuclear diates dyslipidemia induced by the HIV Protease inhibitor amprenavir in mice, cells and their relationship with the expression in intestine and liver, Biochem. Mol. Pharmacol. 83 (2013) 1190–1199. Pharmacol. 70 (2005) 949–958. [87] S. Lang, M. Mary-Krause, L. Cotte, J. Gilquin, M. Partisani, A. Simon, F. Boccara, A. [110] A. Owen, B. Chandler, D.J. Back, S.H. Khoo, Expression of pregnane-X-receptor tran- Bingham, D. Costagliola, Increased risk of myocardial infarction in HIV-infected pa- script in peripheral blood mononuclear cells and correlation with MDR1 mRNA, tients in France, relative to the general population, AIDS 24 (2010) 1228–1230. Antivir. Ther. 9 (2004) 819–821. [88] E.R. Feeney, P.W. Mallon, HIV and HAART-associated dyslipidemia, Open [111] G. Siest, E. Jeannesson, J.B. Marteau, A. Samara, B. Marie, M. Pfister, S. Visvikis-Siest, Cardiovasc. Med. J. 5 (2011) 49–63. Transcription factor and drug-metabolizing enzyme gene expression in lympho- [89] M.L. Ricketts, M.V. Boekschoten, A.J. Kreeft, G.J. Hooiveld, C.J. Moen, M. Muller, R.R. cytes from healthy human subjects, Drug Metab. Dispos. 36 (2008) 182–189. Frants, S. Kasanmoentalib, S.M. Post, H.M. Princen, J.G. Porter, M.B. Katan, M.H. [112] S.C. Casey, B. Blumberg, The steroid and xenobiotic receptor negatively regulates B- Hofker, D.D. Moore, The cholesterol-raising factor from coffee beans, cafestol, as 1 cell development in the fetal liver, Mol. Endocrinol. 26 (2012) 916–925. an agonist ligand for the farnesoid and pregnane X receptors, Mol. Endocrinol. 21 [113] S.C. Casey, E.L. Nelson, G.M. Turco, M.R. Janes, D.A. Fruman, B. Blumberg, B-1 cell (2007) 1603–1616. lymphoma in mice lacking the steroid and xenobiotic receptor, SXR, Mol. [90] T. Li, W. Chen, J.Y. Chiang, PXR induces CYP27A1 and regulates cholesterol metab- Endocrinol. 25 (2011) 933–943. olism in the intestine, J. Lipid Res. 48 (2007) 373–384. [114] N.A. Abumrad, M.R. el-Maghrabi, E.Z. Amri, E. Lopez, P.A. Grimaldi, Cloning of a rat [91] X. Ma, Y.M. Shah, G.L. Guo, T. Wang, K.W. Krausz, J.R. Idle, F.J. Gonzalez, Rifaximin is adipocyte membrane protein implicated in binding or transport of long-chain fatty a gut-specific human pregnane X receptor activator, J. Pharmacol. Exp. Ther. 322 acids that is induced during preadipocyte differentiation. Homology with human (2007) 391–398. CD36, J Biol Chem 268 (1993) 17665–17668. [92] Y. Sui, R.N. Helsley, S.H. Park, X. Song, Z. Liu, C. Zhou, Intestinal pregnane x receptor [115] M. Febbraio, E.A. Podrez, J.D. Smith, D.P. Hajjar,S.L.Hazen,H.F.Hoff,K.Sharma,R.L. links xenobiotic exposure and hypercholesterolemia, Mol. Endocrinol. 29 (2015) Silverstein, Targeted disruption of the class B scavenger receptor CD36 protects against 765–776. atherosclerotic lesion development in mice, J. Clin. Invest. 105 (2000) 1049–1056. [93] A. Takeshita, J. Igarashi-Migitaka, K. Nishiyama, H. Takahashi, Y. Takeuchi, N. [116] K.J. Moore, V.V. Kunjathoor, S.L. Koehn, J.J. Manning, A.A. Tseng, J.M. Silver, M. Koibuchi, Acetyl tributyl citrate, the most widely used phthalate substitute plasti- McKee, M.W. Freeman, Loss of receptor-mediated lipid uptake via scavenger re- cizer, induces cytochrome p450 3a through steroid and xenobiotic receptor, ceptor A or CD36 pathways does not ameliorate atherosclerosis in hyperlipidemic Toxicol. Sci. 123 (2011) 460–470. mice, J. Clin. Invest. 115 (2005) 2192–2201. [94] H.R. Davis Jr., L.J. Zhu, L.M. Hoos, G. Tetzloff, M. Maguire, J. Liu, X. Yao, S.P. Iyer, M.H. [117] E. Guy, S. Kuchibhotla, R. Silverstein, M. Febbraio, Continued inhibition of athero- Lam, E.G. Lund, P.A. Detmers, M.P. Graziano, S.W. Altmann, Niemann-pick C1 like 1 sclerotic lesion development in long term Western diet fed CD36o/apoEo mice, (NPC1L1) is the intestinal phytosterol and cholesterol transporter and a key Atherosclerosis 192 (2007) 123–130.

[118] S.O. Rahaman, D.J. Lennon, M. Febbraio, E.A. Podrez, S.L. Hazen, R.L. Silverstein, A [137] R. Gareus, E. Kotsaki, S. Xanthoulea, I. van der Made, M.J. Gijbels, R. Kardakaris, A. CD36-dependent signaling cascade is necessary for macrophage foam cell forma- Polykratis, G. Kollias, M.P. de Winther, M. Pasparakis, Endothelial cell-specificNF- tion, Cell Metab. 4 (2006) 211–221. kappaB inhibition protects mice from atherosclerosis, Cell Metab. 8 (2008) [119] Y. Sui, J. Xu, J. Rios-Pilier, C. Zhou, Deficiency of PXR decreases atherosclerosis in 372–383. apoE-deficient mice, J. Lipid Res. 52 (2011) 1652–1659. [138] E. Kanters, M. Pasparakis, M.J. Gijbels, M.N. Vergouwe, I. Partouns-Hendriks, R.J. [120] F.S. vom Saal, B.T. Akingbemi, S.M. Belcher, L.S. Birnbaum, D.A. Crain, M. Eriksen, F. Fijneman, B.E. Clausen, I. Forster, M.M. Kockx, K. Rajewsky, G. Kraal, M.H. Hofker, Farabollini, L.J. Guillette Jr., R. Hauser, J.J. Heindel, S.M. Ho, P.A. Hunt, T. Iguchi, S. M.P. de Winther, Inhibition of NF-kappaB activation in macrophages increases ath- Jobling, J. Kanno, R.A. Keri, K.E. Knudsen, H. Laufer, G.A. LeBlanc, M. Marcus, J.A. erosclerosis in LDL receptor-deficient mice, J. Clin. Invest. 112 (2003) 1176–1185. McLachlan, J.P. Myers, A. Nadal, R.R. Newbold, N. Olea, G.S. Prins, C.A. Richter, B.S. [139] S.H. Park, Y. Sui, F. Gizard, J. Xu, J. Rios-Pilier, R.N. Helsley, S.S. Han, C. Zhou, Rubin, C. Sonnenschein, A.M. Soto, C.E. Talsness, J.G. Vandenbergh, L.N. Myeloid-specific IkappaB kinase beta deficiency decreases atherosclerosis in Vandenberg, D.R. Walser-Kuntz, C.S. Watson, W.V. Welshons, Y. Wetherill, R.T. low-density lipoprotein receptor-deficient mice, Arterioscler. Thromb. Vasc. Biol. Zoeller, Chapel Hill bisphenol A expert panel consensus statement: integration of 32 (2012) 2869–2876. mechanisms, effects in animals and potential to impact human health at current [140] Y. Sui, S.H. Park, J. Xu, S. Monette, R.N. Helsley, S.S. Han, C. Zhou, IKKbeta links vas- levels of exposure, Reprod. Toxicol. 24 (2007) 131–138. cular inflammation to obesity and atherosclerosis, J. Exp. Med. 211 (2014) [121] L.N. Vandenberg, M.V. Maffini, C. Sonnenschein, B.S. Rubin, A.M. Soto, Bisphenol-A 869–886. and the great divide: a review of controversies in the field of endocrine disruption, [141] K.A. Hagedorn, C.L. Cooke, J.R. Falck, B.F. Mitchell, S.T. Davidge, Regulation of vascu- Endocr. Rev. 30 (2009) 75–95. lar tone during pregnancy: a novel role for the pregnane X receptor, Hypertension [122] L.N. Vandenberg, I. Chahoud, J.J. Heindel, V. Padmanabhan, F.J. Paumgartten, G. 49 (2007) 328–333. Schoenfelder, Urinary, circulating, and tissue biomonitoring studies indicate wide- [142] K.E. Swales, R. Moore, N.J. Truss, A. Tucker, T.D. Warner, M. Negishi, D. Bishop- spread exposure to bisphenol A, Environ. Health Perspect. 118 (2010) 1055–1070. Bailey, Pregnane X receptor regulates drug metabolism and transport in the [123] I.A. Lang, T.S. Galloway, A. Scarlett, W.E. Henley, M. Depledge, R.B. Wallace, D. vasculature and protects from oxidative stress, Cardiovasc. Res. 93 (2012) Melzer, Association of urinary bisphenol a concentration with medical disorders 674–681. and laboratory abnormalities in adults, JAMA 300 (2008) 1303–1310. [143] X. Wang, X. Fang, J. Zhou, Z. Chen, B. Zhao, L. Xiao, A. Liu, Y.S. Li, J.Y. Shyy, Y. Guan, S. [124] D. Melzer, N.E. Rice, C. Lewis, W.E. Henley, T.S. Galloway, Association of urinary Chien, N. Wang, Shear stress activation of nuclear receptor PXR in endothelial de- bisphenol a concentration with heart disease: evidence from NHANES 2003/06, toxification, Proc. Natl. Acad. Sci. U. S. A. 110 (2013) 13174–13179. PLoS One 5 (2010), e8673. [144] S. Wang, T. Lei, K. Zhang, W. Zhao, L. Fang, B. Lai, J. Han, L. Xiao, N. Wang, Xenobiotic [125] D. Melzer, N.J. Osborne, W.E. Henley, R. Cipelli, A. Young, C. Money, P. McCormack, pregnane X receptor (PXR) regulates innate immunity via activation of NLRP3 R. Luben, K.T. Khaw, N.J. Wareham, T.S. Galloway, Urinary bisphenol a concentra- inflammasome in vascular endothelial cells, J. Biol. Chem. 289 (2014) tion and risk of future coronary artery disease in apparently healthy men and 30075–30081. women, Circulation 125 (2012) 1482–1490. [145] V. Delfosse, B. Dendele, T. Huet, M. Grimaldi, A. Boulahtouf, S. Gerbal-Chaloin, B. [126] D. Melzer, P. Gates, N.J. Osborn, W.E. Henley, R. Cipelli, A. Young, C. Money, P. Beucher, D. Roecklin, C. Muller, R. Rahmani, V. Cavailles, M. Daujat-Chavanieu, V. McCormack, P. Schofield, D. Mosedale, D. Grainger, T.S. Galloway, Urinary Vivat, J.M. Pascussi, P. Balaguer, W. Bourguet, Synergistic activation of human bisphenol a concentration and angiography-defined coronary artery stenosis, pregnane X receptor by binary cocktails of pharmaceutical and environmental PLoS One 7 (2012), e43378. compounds, Nat. Commun. 6 (2015) 8089. [127] P.M. Lind, L. Lind, Circulating levels of bisphenol A and phthalates are related to [146] M. Venkatesh, S. Mukherjee, H. Wang, H. Li, K. Sun, A.P. Benechet, Z. Qiu, L. Maher, carotid atherosclerosis in the elderly, Atherosclerosis 218 (2011) 207–213. M.R. Redinbo, R.S. Phillips, J.C. Fleet, S. Kortagere, P. Mukherjee, A. Fasano, J. Le Ven, [128] L.N. Vandenberg, I. Chahoud, V. Padmanabhan, F.J. Paumgartten, G. Schoenfelder, J.K. Nicholson, M.E. Dumas, K.M. Khanna, S. Mani, Symbiotic bacterial metabolites Biomonitoring studies should be used by regulatory agencies to assess human ex- regulate gastrointestinal barrier function via the xenobiotic sensor PXR and toll- posure levels and safety of bisphenol a, Environ. Health Perspect. 118 (2010) like receptor 4, Immunity 41 (2014) 296–310. 1051–1054. [147] C.L. Acerini, I.A. Hughes, Endocrine disrupting chemicals: a new and emerging pub- [129] Y. Sui, S.H. Park, R.N. Helsley, M. Sunkara, F.J. Gonzalez, A.J. Morris, C. Zhou, lic health problem? Arch. Dis. Child. 91 (2006) 633–641. Bisphenol A increases atherosclerosis in pregnane X receptor-humanized ApoE de- [148] A. Bitter, P. Rummele, K. Klein, B.A. Kandel, J.K. Rieger, A.K. Nussler, U.M. Zanger, M. ficient mice, J. Am. Heart Assoc. 3 (2014), e000492. Trauner, M. Schwab, O. Burk, Pregnane X receptor activation and silencing promote [130] P. Libby, Inflammation in atherosclerosis, Nature 420 (2002) 868–874. steatosis of human hepatic cells by distinct lipogenic mechanisms, Arch. Toxicol. 89 [131] Kathryn J. Moore, I. Tabas, macrophages in the pathogenesis of atherosclerosis, Cell, (2015) 2089–2103. 145 (2011) 341–355. [149] A. Roth, R. Looser, M. Kaufmann, S. Blaettler, F. Rencurel, W. Huang, D.D. Moore, [132] M.S. Hayden, S. Ghosh, Shared principles in NF-kappaB signaling, Cell 132 (2008) U.A. Meyer, Regulatory crosstalk between drug metabolism and lipid homeostasis: 344–362. Car and Pxr Increase Insig-1 expression, Mol. Pharmacol. (2008). [133] R.G. Baker, M.S. Hayden, S. Ghosh, NF-kappaB, inflammation, and metabolic dis- [150] K. Yoshinari, H. Ohno, S. Benoki, Y. Yamazoe, Constitutive androstane receptor ease, Cell Metab. 13 (2011) 11–22. transactivates the hepatic expression of mouse Dhcr24 and human DHCR24 [134] C. Zhou, M.M. Tabb, E.L. Nelson, F. Grun, S. Verma, A. Sadatrafiei, M. Lin, S. Mallick, encoding a cholesterogenic enzyme 24-dehydrocholesterol reductase, Toxicol. B.M. Forman, K.E. Thummel, B. Blumberg, Mutual repression between steroid and Lett. 208 (2012) 185–191. xenobiotic receptor and NF-kappaB signaling pathways links xenobiotic metabo- [151] M. Sporstol, G. Tapia, L. Malerod, S.A. Mousavi, T. Berg, Pregnane X receptor- lism and inflammation, J. Clin. Invest. 116 (2006) 2280–2289. agonists down-regulate hepatic ATP-binding cassette transporter A1 and scaven- [135] X. Gu, S. Ke, D. Liu, T. Sheng, P.E. Thomas, A.B. Rabson, M.A. Gallo, W. Xie, Y. Tian, ger receptor class B type I, Biochem. Biophys. Res. Commun. 331 (2005) Role of NF-kappaB in regulation of PXR-mediated gene expression: a mechanism 1533–1541. for the suppression of cytochrome P-450 3 A4 by proinflammatory agents, J. Biol. [152] S. Gotoh, M. Negishi, Statin-activated nuclear receptor PXR promotes SGK2 de- Chem. 281 (2006) 17882–17889. phosphorylation by scaffolding PP2C to induce hepatic gluconeogenesis, Sci. Rep. [136] W. Xie, Y. Tian, Xenobiotic receptor meets NF-kappaB, A collision in the small 5 (2015) 14076. bowel, Cell Metab. 4 (2006) 177–178.

Please cite this article as: C. Zhou, Novel functions of PXR in cardiometabolic disease, Biochim. Biophys. Acta (2016), http://dx.doi.org/10.1016/ j.bbagrm.2016.02.015