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 1st reported in 2001, when it was suggested that LCA and its metabolite, 3-keto-LCA, can directly activate both mouse and human PXR [30,109]. These studies showed that the administration of LCA, a very toxic secondary BA formed inside the intestine, may possibly trigger 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 and other BAs from sinusoidal blood into the hepatocytes, top to hydroxylation by Cyp3a enzymes facilitating excretion [55]. Hence, PXR activation by LCA seems to be adaptive endogenous protection to decrease BA toxicity in cholestasis [110]. A further 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 a number of genes STAT5 Activator list involved in these processes [30]. Hepatic nuclear element four (HNF4) and its coactivator, peroxisome proliferator-activated receptor coactivator (PGC1), are essential transcription aspects for the transcription of CYP7A1 and CYP8B1. Bhalla et al. recommended that ligand-activated PXR PI3Kα Inhibitor Formulation interacts with PGC1, stimulating its dissociation from HNF4 on the promoters of CYP7A1 and CYP8B1 in HepG2 cells [111]. Even so, another report demonstrated that ligand-activated PXR interacts with HNF4, triggering the release of PGC1 to inhibit the transcription of CYP7A1 in human principal hepatocytes [112]. Inside the intestine, the activation of PXR induces fibroblast growth issue 15 (Fgf15; FGF19 in humans), which inhibits BA synthesis by reducing the transcription of Cyp7a1 in 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 significantly inhibited Cyp7a1 mRNA expression in humanized PXR mice, but not in WT mice. In addition, we reported that CYP7A1 mRNA expression was suppressed by treatment with MK-4 in HepG2 cells [8]. Furthermore, PXR can be a regulator of uridine diphosphate glucuronosyltransferase (UGT1A1), an essential 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 to the controls, followed by a substantial boost of SULT2A1 only in PBC, but not in PSC [114]. Staudinger et al. reported that PCN therapy significantly induced Na-independent organic anion transporter 2 (Oatp2) expression in WT mice, but not in PXR knockout mice [30]. Oatp2 can be a basolateral transporter involved within the hepatocellular uptake of a broad-spectrum of amphipathic substrates, including 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., conjugates of LCA), xenobiotics, and their glutathione conjugates into bile; thus, it’s a major determinant of BA-independent bile flow [115]. A significant role of PXR in the regulation of MRP2 in animals a.
