The Nuclear Receptor PXR in Chronic Liver Disease

Overview

Journal Cells

Publisher MDPI

Specialties Biochemistry
Biophysics
Cell Biology
Molecular Biology

Date 2022 Jan 11

PMID 35011625

Authors

Katia Sayaf

Ilaria Zanotto

Francesco Paolo Russo

Daniela Gabbia

Sara De Martin

Affiliations

Soon will be listed here.

Abstract

Pregnane X receptor (PXR), a nuclear receptor known for modulating the transcription of drug metabolizing enzymes and transporters (DMETs), such as cytochrome P450 3A4 and P-glycoprotein, is functionally involved in chronic liver diseases of different etiologies. Furthermore, PXR activity relates to that of other NRs, such as constitutive androstane receptor (CAR), through a crosstalk that in turn orchestrates a complex network of responses. Thus, besides regulating DMETs, PXR signaling is involved in both liver damage progression and repair and in the neoplastic transition to hepatocellular carcinoma. We here summarize the present knowledge about PXR expression and function in chronic liver diseases characterized by different etiologies and clinical outcome, focusing on the molecular pathways involved in PXR activity. Although many molecular details of these finely tuned networks still need to be fully understood, we conclude that PXR and its modulation could represent a promising pharmacological target for the identification of novel therapeutical approaches to chronic liver diseases.

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References

Ronca V, Mancuso C, Milani C, Carbone M, Htun Oo Y, Invernizzi P . Immune system and cholangiocytes: A puzzling affair in primary biliary cholangitis. J Leukoc Biol. 2020; 108(2):659-671. DOI: 10.1002/JLB.5MR0320-200R. View

Mackowiak B, Wang H . Mechanisms of xenobiotic receptor activation: Direct vs. indirect. Biochim Biophys Acta. 2016; 1859(9):1130-1140. PMC: 4975672. DOI: 10.1016/j.bbagrm.2016.02.006. View

Staudinger J, Goodwin B, Jones S, MacKenzie K, LaTour A, Liu Y . The nuclear receptor PXR is a lithocholic acid sensor that protects against liver toxicity. Proc Natl Acad Sci U S A. 2001; 98(6):3369-74. PMC: 30660. DOI: 10.1073/pnas.051551698. View

Li Z, Kruijt J, van der Sluis R, Van Berkel T, Hoekstra M . Nuclear receptor atlas of female mouse liver parenchymal, endothelial, and Kupffer cells. Physiol Genomics. 2013; 45(7):268-75. DOI: 10.1152/physiolgenomics.00151.2012. View

Gabbia D, Dalla Pozza A, Albertoni L, Lazzari R, Zigiotto G, Carrara M . Pregnane X receptor and constitutive androstane receptor modulate differently CYP3A-mediated metabolism in early- and late-stage cholestasis. World J Gastroenterol. 2017; 23(42):7519-7530. PMC: 5698245. DOI: 10.3748/wjg.v23.i42.7519. View

Haughton E, Tucker S, Marek C, Durward E, Leel V, Bascal Z . Pregnane X receptor activators inhibit human hepatic stellate cell transdifferentiation in vitro. Gastroenterology. 2006; 131(1):194-209. DOI: 10.1053/j.gastro.2006.04.012. View

Jia W, Wei M, Rajani C, Zheng X . Targeting the alternative bile acid synthetic pathway for metabolic diseases. Protein Cell. 2020; 12(5):411-425. PMC: 8106556. DOI: 10.1007/s13238-020-00804-9. View

Gulamhusein A, Hirschfield G . Primary biliary cholangitis: pathogenesis and therapeutic opportunities. Nat Rev Gastroenterol Hepatol. 2019; 17(2):93-110. DOI: 10.1038/s41575-019-0226-7. View

Naito H, Jia X, Yetti H, Yanagiba Y, Tamada H, Kitamori K . Importance of detoxifying enzymes in differentiating fibrotic development between SHRSP5/Dmcr and SHRSP rats. Environ Health Prev Med. 2016; 21(5):368-381. PMC: 5305991. DOI: 10.1007/s12199-016-0539-x. View

10.

Karlsen T, Folseraas T, Thorburn D, Vesterhus M . Primary sclerosing cholangitis - a comprehensive review. J Hepatol. 2017; 67(6):1298-1323. DOI: 10.1016/j.jhep.2017.07.022. View

11.

Yan J, Xie W . A brief history of the discovery of PXR and CAR as xenobiotic receptors. Acta Pharm Sin B. 2016; 6(5):450-452. PMC: 5045536. DOI: 10.1016/j.apsb.2016.06.011. View

12.

Cai X, Young G, Xie W . The xenobiotic receptors PXR and CAR in liver physiology, an update. Biochim Biophys Acta Mol Basis Dis. 2021; 1867(6):166101. PMC: 8026720. DOI: 10.1016/j.bbadis.2021.166101. View

13.

Etherington R, Millar B, Innes B, Jones D, Kirby J, Brain J . Bile acid receptor agonists in primary biliary cholangitis: Regulation of the cholangiocyte secretome and downstream T cell differentiation. FASEB Bioadv. 2020; 1(5):332-343. PMC: 6996327. DOI: 10.1096/fba.2018-00046. View

14.

Gabbia D, Roverso M, Guido M, Sacchi D, Scaffidi M, Carrara M . Western Diet-Induced Metabolic Alterations Affect Circulating Markers of Liver Function before the Development of Steatosis. Nutrients. 2019; 11(7). PMC: 6683046. DOI: 10.3390/nu11071602. View

15.

Halgren T . Identifying and characterizing binding sites and assessing druggability. J Chem Inf Model. 2009; 49(2):377-89. DOI: 10.1021/ci800324m. View

16.

Pierantonelli I, Svegliati-Baroni G . Nonalcoholic Fatty Liver Disease: Basic Pathogenetic Mechanisms in the Progression From NAFLD to NASH. Transplantation. 2018; 103(1):e1-e13. DOI: 10.1097/TP.0000000000002480. View

17.

Kotiya D, Jaiswal B, Ghose S, Kaul R, Datta K, Tyagi R . Role of PXR in Hepatic Cancer: Its Influences on Liver Detoxification Capacity and Cancer Progression. PLoS One. 2016; 11(10):e0164087. PMC: 5070842. DOI: 10.1371/journal.pone.0164087. View

18.

Wright M . The impact of pregnane X receptor activation on liver fibrosis. Biochem Soc Trans. 2006; 34(Pt 6):1119-23. DOI: 10.1042/BST0341119. View

19.

Goldstein J, Levy C . Novel and emerging therapies for cholestatic liver diseases. Liver Int. 2018; 38(9):1520-1535. DOI: 10.1111/liv.13880. View

20.

Zhou H, Hylemon P . Bile acids are nutrient signaling hormones. Steroids. 2014; 86:62-8. PMC: 4073476. DOI: 10.1016/j.steroids.2014.04.016. View