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ABC Transporters, Organic Solute Carriers and Drug Metabolising Enzymes in Bile Duct Epithelial Cells
Published in Gianfranco Alpini, Domenico Alvaro, Marco Marzioni, Gene LeSage, Nicholas LaRusso, The Pathophysiology of Biliary Epithelia, 2020
Expression of organic solute carriers and ABC transporters in hepatocytes is transcriptionally and post-translationally regulated.47,48 For the transcriptional regulation nuclear hormone receptors are important.2 These are ligand-activated transcription factors that upon activation with an appropriate ligand form dimers with the retinoid binding receptor RXR and these heterodimers then bind to the promoter region of transporter genes. BSEP and a gene called small heterodimer partner SHP, are target genes for the farnesoid X-receptor FXR.49–51 FXR is activated by bile salts and this leads to increased transcription of BSEP and SHP. BSEP expression is subsequendy increased and canalicular bile salt transport is enhanced. The SHP-protein negatively interacts with the binding of LRH-1 to the genes encoding NTCP and cholesterol 7a-hydroxylase or CYP7A1 .49,52–55 Transcription of these genes is impaired and as a consequence bile salt uptake and de novo bile acid synthesis are reduced.
Tyrosine Phosphatases as New Treatment Targets in Acute Myeloid Leukemia
Published in Gertjan J. L. Kaspers, Bertrand Coiffier, Michael C. Heinrich, Elihu Estey, Innovative Leukemia and Lymphoma Therapy, 2019
I. Hubeek, K. Hoorweg, J. Cloos, Gertjan J. L. Kaspers
Furthermore, there are good indications that lowered SHP-1 expression is indicative of a more aggressive hematopoietic disease. In CML for instance, Bcr-Abl is inhibited by SHP-1. In advanced stage CML patients, SHP-1 levels are markedly decreased compared with patients in chronic phase, possibly by posttranslational modifications. Decrease of SHP-1 levels therefore plays a role in the progression of CML and could provide an explanation for imatinib resistance seen in advanced stage CML patients (73). In solid tumors such as prostate cancer, ovarian, pancreatic and breast cancer, however, overexpression of SHP-1 has been observed, as reviewed by Wu et al. (57).
Regulation of Human CYP2D6
Published in Shufeng Zhou, Cytochrome P450 2D6, 2018
SHP, a unique orphan nuclear receptor that contains a dimerization and ligand-binding domain but lacks the conserved DNA-binding domain, can repress other nuclear receptors through the formation of a nonproductive heterodimer that can directly compete with coactivators or acts via direct effects of its transcriptional repressor function (Bavner et al. 2005; Goodwin et al. 2000; Johansson et al. 2000; Lee et al. 1998; Seol et al. 1996, 1997, 1998). SHP is predominantly observed in the liver. Nuclear receptors that can be suppressed by SHP include RARa, RXRα, AhR, FXR, LXRα, HNF-4α, PPARAγ, androgen and estrogen receptors, growth hormone receptors, and thyroid hormone receptors (Brendel et al. 2002; Goodwin et al. 2000; Hoeke et al. 2014; Johansson et al. 2000; Kassam et al. 2001; Kim et al. 2012; Klinge et al. 2001; Lee and Moore 2002; Lee et al. 1998, 2000; Mamoon et al. 2014; Ning et al. 2015; Ourlin et al. 2003; Seol et al. 1996, 1997, 1998; Vaquero et al. 2013; Yang et al. 2015; Zhang et al. 2015; Zhi et al. 2014). As such, SHP can regulate the expression of CYP2D6 via inhibition of nuclear receptors.
Odevixibat: an investigational inhibitor of the ileal bile acid transporter (IBAT) for the treatment of biliary atresia
Published in Expert Opinion on Investigational Drugs, 2022
As well as digestion, bile acids have auto- and paracrine effects on the signaling of nuclear receptors to maintain bile acid homeostasis: the Farnesoid X receptor (FXR), strongly expressed in ileal enterocytes and hepatocytes, can be activated by bile acids [14]. Activation of FXR in enterocytes leads to the production of fibroblast growth factor 19 (FGF19). After circulation to the liver via the portal blood, FGF19 activates fibroblast growth factor receptor 4 (FGFR4/beta-klotho) and thus inhibits CYP7A1 [15]. In addition, stimulation of FXR by bile acids in hepatocytes induces the small heterodimer partner (SHP), leading to a repression of CYP7A1 and resulting in less production of bile acids [14]. Alongside inhibition of CYP7A1, FXR activation induces the expression of BSEP, as well as inhibiting the expression of NTCP, resulting in decreased cellular bile acid accumulation [15] (Box 1).
Emerging drugs for the treatment of non-alcoholic steatohepatitis: a focused review of farnesoid X receptor agonists
Published in Expert Opinion on Emerging Drugs, 2020
Raj A. Shah, Naim Alkhouri, Kris V Kowdley
FXR is expressed highly in the liver, ileum, kidney, and adrenal glands, and has been found to play a key role in bile acid and lipid metabolism [3]. An overview of the effects of FXR relevant to NASH is shown in Figure 1. In hepatocytes, FXR induces expression of small heterodimer partner (SHP), an orphan family nuclear receptor, which leads to inhibited transcription of sterol regulatory element factor binding protein-1 c (SREBP-1 c) [66]. SREBP-1 c has been shown to play a role in upregulating enzymes responsible for lipogenesis [66]. FXR in ileal enterocytes upregulates expression of FGF-19, a protein that binds a fibroblast growth factor receptor 4 (FGFR4)/βKlotho receptor complex in hepatocytes [67]. FGF-19 activates hepatic glycogen and protein synthesis [68] while inhibiting bile acid synthesis [67]. FXR may also crosstalk with PPAR-α, evidenced by the discovery of a FXR response element in the promoter of the gene encoding PPAR-α along with demonstration of FXR agonism leading to increased PPAR-α expression [69]. Target genes of PPAR-α include medium-chain acyl-coenzyme a and acyl-CoA oxidase 1, which are rate-limiting enzymes for fatty acid beta oxidation pathways, indicating that PPAR-α upregulates fatty acid catabolism [70]. Additionally, PPAR-α has been shown to increase expression of FGF-21, which leads to enhanced expression of glucose transporter 1 in extrahepatic tissue, improving basal glucose uptake [70].
Expression of cytochrome P450 regulators in cynomolgus macaque
Published in Xenobiotica, 2018
Yasuhiro Uno, Hiroshi Yamazaki
Cynomolgus SHP mRNA showed correlations with HNF4α and PXR mRNAs (Table 4), possibly reflecting regulation of SHP by HNF4α and PXR as in humans (Zhang et al., 2011). SHP forms a heterodimer with CAR, ERα, FXR, GR, HNF4α, LXRα, PPARα, PPARγ, PXR, and RXRα among others to act as a transcription repressor because SHP lacks a DNA-binding domain and inhibits the function of the bound nuclear receptors (Zhang et al., 2011). Cynomolgus GR mRNA showed correlations with CYP2C8, CYP2C9, CYP2C19, CYP3A4, CYP3A5, CAR, PXR, and RXRα mRNAs (Tables 4 and 5), possibly due to regulation of these P450s and regulators by GR. Similarly, human GR is involved in regulation of P450s including CYP2C9 and CYP3A4 (Dvorak & Pavek 2010; Tirona & Kim 2005). Cynomolgus HNF1α mRNA showed correlations with FXR, HNF4α, and PXR mRNAs (Table 4), possibly reflecting regulation of these P450 regulators by HNF1α as in humans (Dixit et al., 2005). Cynomolgus AHR mRNA showed correlations with CAR mRNA (Table 4), possibly due to regulation of CAR by AHR, also similar to humans (Köhle & Bock, 2009).