PREGNANE X RECEPTOR REGULATION OF BILE ACID METABOLISM AND CHOLESTEROL HOMEOSTASIS

PREGNANE X RECEPTOR REGULATION OF BILE ACID METABOLISM AND CHOLESTEROL HOMEOSTASIS

Bibliographic Details
Main Author: Li, Tiangang
Language:English
Published: Kent State University / OhioLINK 2006
Subjects:
PXR
BILE
BILE ACID
HNF4¿¿¿¿
CYP7A1
CHOLESTEROL
rifampicin
Online Access:http://rave.ohiolink.edu/etdc/view?acc_num=kent1132160196
id ndltd-OhioLink-oai-etd.ohiolink.edu-kent1132160196
record_format oai_dc
spelling ndltd-OhioLink-oai-etd.ohiolink.edu-kent11321601962021-08-03T05:36:13Z PREGNANE X RECEPTOR REGULATION OF BILE ACID METABOLISM AND CHOLESTEROL HOMEOSTASIS Li, Tiangang PXR BILE BILE ACID HNF4¿¿¿¿ CYP7A1 CHOLESTEROL rifampicin The nuclear receptor pregnane X receptor (PXR) is activated by bile acids, steroids and drugs and regulates a network of genes in lipid and drug mechanisms. The goal of this study is to investigate the role of PXR in the coordinate regulation of bile acid synthetic and detoxification genes and its implications in cholestatic liver diseases and treatments. Cholesterol 7alpha hydroxylase (CYP7A1) catalyzes the rate-limiting step in the classic bile acids synthetic pathway and plays a key role in controlling bile acids homeostasis. Quantitative real-time PCR (Q-PCR) showed human PXR agonist rifampicin inhibited CYP7A1 mRNA expression in primary human hepatocytes. Mammalian two-hybrid assays, co-immunoprecipitation (co-IP) assays and chromatin immunoprecipitation (ChIP) assay revealed that ligand-activated PXR strongly interacted with HNF4alpha, the key activator of human CYP7A1, and blocked HNF4alpha interaction with co-activator PGC-1alpha, thus resulted in inhibition of CYP7A1. CYP3A4 is the most abundant cytochrome P450 monooxygenase expressed in human liver and intestine. Bile acids and drugs-activated PXR induces CYP3A4, which converts toxic bile acids to non-toxic metabolites for excretion. Studies using Q-PCR, reporter assays, GST pull-down assays and ChIP assays revealed that PXR strongly induced CYP3A4 gene transcription by interacting with HNF4alpha, SRC-1 and PGC-1alpha. SHP, a negative nuclear receptor, reduced PXR recruitment of HNF4alpha and SRC-1 to the CYP3A4 chromatin and inhibited CYP3A4. Interestingly, PXR concomitantly inhibited SHP gene transcription and maximized the PXR induction of CYP3A4. Taken together, PXR inhibits CYP7A1 to reduce bile acid synthesis and induces CYP3A4 to detoxify bile acid. Thus, PXR may play a protective role against cholestasis. Drugs targeted to PXR may be developed for treating cholestatic liver diseases induced by bile acids and drugs. Mitochondrial sterol 27-hydroxylase (CYP27A1) catalyzes the side-chain cleavage reaction in bile acid synthetic pathways and 27-hydroxylation of cholesterol mainly in the peripheral tissues. Q-PCR revealed that rifampicin induced CYP27A1 mRNA expression in the intestine-derived Caco2 cells, but not in primary human hepatocytes and HepG2 cells. Rifampicin stimulated CYP27A1 gene transcription in cholesterol laden Caco2 cells and increased intracellular 27HOC, which stimulates cholesterol efflux by induction of cholesterol efflux transporters ABCA1 and ABCG1. Mutagenesis analysis, electrophoretic mobility shift assay and ChIP assays identified a functional PXR binding site in the human CYP27A1 gene. These data suggest that 27-hydroxycholesterol is an endogenous LXRalpha ligand and the PXR/CYP27A1/LXRalpha signaling pathway regulate cholesterol efflux in intestine cells. Results revealed an intestine-specific regulation of human CYP27A1 gene by PXR and suggested a novel role for PXR in cholesterol metabolism and detoxification in the intestine. 2006 English text Kent State University / OhioLINK http://rave.ohiolink.edu/etdc/view?acc_num=kent1132160196 http://rave.ohiolink.edu/etdc/view?acc_num=kent1132160196 unrestricted This thesis or dissertation is protected by copyright: all rights reserved. It may not be copied or redistributed beyond the terms of applicable copyright laws.
collection NDLTD
language English
sources NDLTD
topic PXR
BILE
BILE ACID
HNF4¿¿¿¿
CYP7A1
CHOLESTEROL
rifampicin
spellingShingle PXR
BILE
BILE ACID
HNF4¿¿¿¿
CYP7A1
CHOLESTEROL
rifampicin
Li, Tiangang
PREGNANE X RECEPTOR REGULATION OF BILE ACID METABOLISM AND CHOLESTEROL HOMEOSTASIS
author Li, Tiangang
author_facet Li, Tiangang
author_sort Li, Tiangang
title PREGNANE X RECEPTOR REGULATION OF BILE ACID METABOLISM AND CHOLESTEROL HOMEOSTASIS
title_short PREGNANE X RECEPTOR REGULATION OF BILE ACID METABOLISM AND CHOLESTEROL HOMEOSTASIS
title_full PREGNANE X RECEPTOR REGULATION OF BILE ACID METABOLISM AND CHOLESTEROL HOMEOSTASIS
title_fullStr PREGNANE X RECEPTOR REGULATION OF BILE ACID METABOLISM AND CHOLESTEROL HOMEOSTASIS
title_full_unstemmed PREGNANE X RECEPTOR REGULATION OF BILE ACID METABOLISM AND CHOLESTEROL HOMEOSTASIS
title_sort pregnane x receptor regulation of bile acid metabolism and cholesterol homeostasis
publisher Kent State University / OhioLINK
publishDate 2006
url http://rave.ohiolink.edu/etdc/view?acc_num=kent1132160196
work_keys_str_mv AT litiangang pregnanexreceptorregulationofbileacidmetabolismandcholesterolhomeostasis
_version_ 1719422350745665536

Similar Items