Dicate induction; bars indicate inhibition; ellipses denote receptors; cylinders denote transporters
Dicate induction; bars indicate inhibition; ellipses denote receptors; cylinders denote transporters; and broken line boxes denote enzymes.The function of PXR in BA homeostasis was initially reported in 2001, when it was suggested that LCA and its metabolite, α2β1 Inhibitor drug 3-keto-LCA, can straight activate each mouse and human PXR [30,109]. These studies showed that the administration of LCA, a hugely toxic secondary BA formed within the intestine, could result in intrahepatic cholestasis. Pharmacological stimulation of PXR improves LCA-induced liver toxicity. When activated by LCA and its metabolite, PXR inhibits Cyp7a1 that blocks BA synthesis and increases the uptake ofNutrients 2021, 13,11 ofLCA as well as other BAs from sinusoidal blood in to the hepatocytes, leading to hydroxylation by Cyp3a enzymes facilitating excretion [55]. As a result, PXR activation by LCA seems to become adaptive endogenous protection to decrease BA toxicity in cholestasis [110]. An additional study reported that the activation of PXR by PCN strongly induced the BA-hydroxylating enzymes Cyp3a11 (in human CYP3A4) and Cyp2b10 [105]. It was demonstrated that PXR activation regulates the biosynthesis, transport, and metabolism of BAs in mice by modulating many genes involved in these processes [30]. Hepatic nuclear aspect 4 (HNF4) and its coactivator, peroxisome proliferator-activated receptor coactivator (PGC1), are essential transcription components for the transcription of CYP7A1 and CYP8B1. Bhalla et al. suggested that ligand-activated PXR interacts with PGC1, stimulating its dissociation from HNF4 around the promoters of CYP7A1 and CYP8B1 in HepG2 cells [111]. Having said that, one more report demonstrated that ligand-activated PXR interacts with HNF4, triggering the release of PGC1 to inhibit the transcription of CYP7A1 in human main hepatocytes [112]. Inside the intestine, the activation of PXR induces fibroblast development aspect 15 (Fgf15; FGF19 in humans), which inhibits BA synthesis by lowering the transcription of Cyp7a1 inside the liver [110]. In 2009, it was demonstrated that CYP3A4 promoter activity was enhanced by MK-4 mediated stimulation of PXR. In 2018, we showed that MK-4 therapy substantially inhibited Cyp7a1 mRNA expression in humanized PXR mice, but not in WT mice. Moreover, we reported that CYP7A1 mRNA expression was suppressed by treatment with MK-4 in HepG2 cells [8]. Additionally, PXR is usually a regulator of uridine diphosphate glucuronosyltransferase (UGT1A1), an important phase II enzyme for bilirubin glucuronidation and sulfotransferase 2A1 (SUL2A1), and hydroxysteroid sulfotransferase, which increases the solubility of BAs [105,113]. In each PSC and PBC, increased PXR protein was observed in comparison with the controls, followed by a significant boost of SULT2A1 only in PBC, but not in PSC [114]. Staudinger et al. reported that PCN remedy substantially induced Na-independent organic anion transporter 2 (Oatp2) expression in WT mice, but not in PXR knockout mice [30]. Oatp2 is actually a basolateral transporter involved inside the hepatocellular uptake of a broad-spectrum of amphipathic substrates, which includes BAs. The canalicular multi-specific organic anion transporter (cMOAT, multidrug resistance protein 2, or MRP2) can transport several compounds, like bilirubin diglucuronide, sulfates, some BAs (e.g., TrkC Inhibitor supplier conjugates of LCA), xenobiotics, and their glutathione conjugates into bile; therefore, it is a major determinant of BA-independent bile flow [115]. A considerable function of PXR in the regulation of MRP2 in animals a.