scholarly journals Xenobiotic Nuclear Receptor Signaling Determines Molecular Pathogenesis of Progressive Familial Intrahepatic Cholestasis

Endocrinology ◽  
2018 ◽  
Vol 159 (6) ◽  
pp. 2435-2446 ◽  
Author(s):  
Kang Ho Kim ◽  
Jong Min Choi ◽  
Feng Li ◽  
Armando Arizpe ◽  
Clavia Ruth Wooton-Kee ◽  
...  
Keyword(s):  
Liver Injury ◽  
Intrahepatic Cholestasis ◽  
Constitutive Androstane Receptor ◽  
Pregnane X Receptor ◽  
Acid Synthesis ◽  
Molecular Pathogenesis ◽  
Farnesoid X Receptor ◽  
Loss Of Function ◽  
Double Knockout ◽  
Progressive Familial Intrahepatic Cholestasis

Abstract Progressive familial intrahepatic cholestasis (PFIC) is a genetically heterogeneous disorder of bile flow disruption due to abnormal canalicular transport or impaired bile acid (BA) metabolism, causing excess BA accumulation and liver failure. We previously reported an intrahepatic cholestasis mouse model based on loss of function of both farnesoid X receptor (FXR; NR1H4) and a small heterodimer partner (SHP; NR0B2) [double knockout (DKO)], which has strong similarities to human PFIC5. We compared the pathogenesis of DKO livers with that of another intrahepatic cholestasis model,Bsep−/−, which represents human PFIC2. Both models exhibit severe hepatomegaly and hepatic BA accumulation, but DKO showed greater circulating BA and liver injury, andBsep−/− had milder phenotypes. Molecular profiling of BAs uncovered specific enrichment of cholic acid (CA)–derived BAs in DKO livers but chenodeoxycholate-derived BAs inBsep−/− livers. Transcriptomic and proteomic analysis revealed specific activation of CA synthesis and alternative basolateral BA transport in DKO but increased chenodeoxycholic acid synthesis and canalicular transport inBsep−/−. The constitutive androstane receptor (CAR)/pregnane X receptor (PXR)–CYP2B/CYP2C axis is activated in DKO livers but not in other cholestasis models. Loss of this axis inFxr:Shp:Car:Pxr quadruple knockouts blockedCyp2b/Cyp2c gene induction, impaired bilirubin conjugation/elimination, and increased liver injury. Differential CYP2B expression in DKO andBsep−/− was recapitulated in human PFIC5 and PFIC2 livers. In conclusion, loss of FXR/SHP results in distinct molecular pathogenesis and CAR/PXR activation, which promotesCyp2b/Cyp2c gene transcription and bilirubin clearance. CAR/PXR activation was not observed inBsep−/− mice or PFIC2 patients. These findings provide a deeper understanding of the heterogeneity of intrahepatic cholestasis.

Knockdown of ATP8B1 expression leads to specific downregulation of the bile acid sensor FXR in HepG2 cells: effect of the FXR agonist GW4064

2009 ◽  
Vol 296 (5) ◽  
pp. G1119-G1129 ◽  
Author(s):  
Pilar Martínez-Fernández ◽  
Loreto Hierro ◽  
Paloma Jara ◽  
Luis Alvarez
Keyword(s):  
Bile Acid ◽  
Hepg2 Cells ◽  
Target Genes ◽  
Constitutive Androstane Receptor ◽  
Pregnane X Receptor ◽  
Acid Synthesis ◽  
Bile Acid Synthesis ◽  
Bile Secretion ◽  
Farnesoid X Receptor ◽  
Mrna Levels

Farnesoid X receptor (FXR) is a bile acid-sensing nuclear receptor that controls bile acid homeostasis. It has been suggested that downregulation of FXR contributes to the pathogenesis of an inherited disorder of bile secretion caused by mutations in ATP8B1. We have investigated the relationship between ATP8B1 knockdown and FXR downregulation in the human hepatoblastoma cell line HepG2. Transfection of HepG2 cells with ATP8B1 small interfering RNA (siRNA) duplexes led to a 60% reduction in the endogenous levels of ATP8B1 mRNA and protein and a concomitant decrease in FXR mRNA and protein content, as well as in FXR phosphorylation. This decrease was accompanied by a marked reduction in mRNA levels of a subset of FXR targets, such as bile salt export pump ( ABCB11), small heterodimer partner, and uridine 5′-diphosphate-glucuronosyltransferase. ATP8B1 inhibition specifically targeted FXR since mRNA expression of other prominent nuclear receptors, such as pregnane X receptor and constitutive androstane receptor, or liver-enriched transcription factors, such as hepatocyte nuclear factor 1α ( HNF-1α) and HNF-4α, was not altered. The expression of other key genes involved in bile acid synthesis, detoxification, and transport also remained unchanged upon ATP8B1 knockdown. Supporting the specificity of the effect, siRNA-mediated silencing of ABCB11, whose defect is associated with another inherited disorder of bile secretion, did not affect FXR expression. Treatment with the synthetic FXR agonist GW4064 was able to partially neutralize ATP8B1 siRNA-mediated FXR downregulation and fully counteract inhibition of FXR target genes. Collectively these findings indicate that ATP8B1 knockdown specifically downregulates FXR, and this action can be circumvented by treatment with FXR agonists.

scholarly journals Progressive familial intrahepatic cholestasis — farnesoid X receptor deficiency due to NR1H4 mutation: A case report

2021 ◽  
Vol 9 (15) ◽  
pp. 3631-3636
Author(s):  
Piotr Czubkowski ◽  
Richard J Thompson ◽  
Irena Jankowska ◽  
A S Knisely ◽  
Milton Finegold ◽  
...  
Keyword(s):  
Case Report ◽  
Intrahepatic Cholestasis ◽  
Farnesoid X Receptor ◽  
Progressive Familial Intrahepatic Cholestasis

scholarly journals The Decrease in Farnesoid X Receptor, Pregnane X Receptor and Constitutive Androstane Receptor in the Liver after Intestinal Ischemia-Reperfusion

2012 ◽  
Vol 15 (5) ◽  
pp. 616 ◽  
Author(s):  
Jiro Ogura ◽  
Yusuke Terada ◽  
Takashi Tsujimoto ◽  
Takahiro Koizumi ◽  
Kaori Kuwayama ◽  
...  
Keyword(s):  
Western Blotting ◽  
Hepg2 Cells ◽  
Intestinal Ischemia ◽  
Ischemia Reperfusion ◽  
Constitutive Androstane Receptor ◽  
Pregnane X Receptor ◽  
Farnesoid X Receptor ◽  
Expression Levels ◽  
Intestinal Ischemia Reperfusion

Purpose. Intestinal ischemia-reperfusion (I/R) damages remote organs, including the liver, and promotes multi-organ failure (MOF). However, the molecular mechanisms underlying acute liver injury after intestinal I/R have not been completely elucidated. Farnesoid X receptor (FXR), pregnane X receptor (PXR) and constitutive androstane receptor (CAR) regulate metabolizing enzymes and transporters, and coordinately prevent hepatotoxicity reflecting an inability of appropriate excretion of endogenous toxic compounds. In this study, we assessed FXR, PXR and CAR expression levels and their localization levels in nuclei in the liver after intestinal I/R. We also investigated the effect of IL-6 on FXR, PXR and CAR expression levels and their localization levels in nuclei in in vitro experiments. Methods. We used intestinal I/R model rats. Moreover, HepG2 cells were used in in vitro study. Real-time PCR and Western blotting were used to assess mRNA and protein expression levels. Nuclear receptor localization in nuclei was analyzed by Western blotting using nuclear extracts. Results. FXR and PXR expression levels began to be decreased at 3 h, and FXR, PXR and CAR expression levels were decreased at 6 h after intestinal I/R. The localization levels of FXR, PXR and CAR in nuclei began to be decreased at 3 h, and all of them were decreased at 6 h after intestinal I/R. In HepG2 cells, FXR, PXR and CAR expression levels were decreased by 0.5-1 ng/mL, 0.5-100 ng/mL and 100 ng/mL IL-6 treatment for 24 h, respectively. FXR, PXR and CAR localization levels in nuclei were suppressed by 0.5-10 ng/mL, 10-100 ng/mL and 10-100 ng/mL IL-6 treatment for 24 h, respectively. Conclusions. FXR, PXR and CAR expression levels are decreased in the liver after intestinal I/R. IL-6 is one of main causes the decreases in expressions of these receptors. This article is open to POST-PUBLICATION REVIEW. Registered readers (see “For Readers”) may comment by clicking on ABSTRACT on the issue’s contents page.

scholarly journals Promoter DNA Methylation of Farnesoid X Receptor and Pregnane X Receptor Modulates the Intrahepatic Cholestasis of Pregnancy Phenotype

PLoS ONE ◽  
2014 ◽  
Vol 9 (1) ◽  
pp. e87697 ◽  
Author(s):  
Romina Cabrerizo ◽  
Gustavo O. Castaño ◽  
Adriana L. Burgueño ◽  
Tomas Fernández Gianotti ◽  
María Mora Gonzalez Lopez Ledesma ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Intrahepatic Cholestasis ◽  
Pregnane X Receptor ◽  
Farnesoid X Receptor ◽  
Intrahepatic Cholestasis Of Pregnancy ◽  
Promoter Dna Methylation ◽  
Promoter Dna ◽  
Cholestasis Of Pregnancy

scholarly journals Nuclear Receptor Metabolism of Bile Acids and Xenobiotics: A Coordinated Detoxification System with Impact on Health and Diseases

2018 ◽  
Vol 19 (11) ◽  
pp. 3630 ◽  
Author(s):  
Manon Garcia ◽  
Laura Thirouard ◽  
Lauriane Sedès ◽  
Mélusine Monrose ◽  
Hélène Holota ◽  
...  
Keyword(s):  
Transcriptional Control ◽  
Constitutive Androstane Receptor ◽  
Pregnane X Receptor ◽  
Nuclear Hormone Receptor ◽  
Farnesoid X Receptor ◽  
Metabolizing Enzymes ◽  
Functional Studies ◽  
Endogenous Metabolites ◽  
Pathologic Processes

Structural and functional studies have provided numerous insights over the past years on how members of the nuclear hormone receptor superfamily tightly regulate the expression of drug-metabolizing enzymes and transporters. Besides the role of the farnesoid X receptor (FXR) in the transcriptional control of bile acid transport and metabolism, this review provides an overview on how this metabolic sensor prevents the accumulation of toxic byproducts derived from endogenous metabolites, as well as of exogenous chemicals, in coordination with the pregnane X receptor (PXR) and the constitutive androstane receptor (CAR). Decrypting this network should provide cues to better understand how these metabolic nuclear receptors participate in physiologic and pathologic processes with potential validation as therapeutic targets in human disabilities and cancers.

scholarly journals Molecular cloning and regulation of porcine SULT2A1: relationship between SULT2A1 expression and sulfoconjugation of androstenone

2006 ◽  
Vol 36 (2) ◽  
pp. 301-311 ◽  
Author(s):  
P A Sinclair ◽  
W J Gilmore ◽  
Z Lin ◽  
Y Lou ◽  
E J Squires
Keyword(s):  
Constitutive Androstane Receptor ◽  
Pregnane X Receptor ◽  
Farnesoid X Receptor ◽  
Boar Taint ◽  
Regulatory Control ◽  
Pcr Analysis ◽  
Coding Region ◽  
Positive Role ◽  
Low Levels

Hydroxysteroid sulfotransferase (SULT2A1) is a key enzyme in the testicular and hepatic metabolism of 5α-androstenone, which is a major component of the off-odor and off-flavor in pork known as boar taint. The goals of this study were to determine the role of testicular and hepatic SULT2A1 activity on plasma 5α-androstenone sulfate levels, the accumulation of 5α-androstenone in adipose tissue, and to gain insight into the regulatory control of SULT2A1. Testicular SULT2A1 activity was negatively correlated (r= −0.57; P<0.01) with 5α-androstenone concentrations in fat. The differences observed in SULT2A1 activity warranted investigation into potential genetic variation within porcine SULT2A1. The cDNA sequence of porcine Sult2A1 was determined to be >82% homologous to the human, mouse, and rat Sult2A1 genes. A single nucleotide polymorphism was detected within the coding region of the Sult2A1 from individual testes and liver samples; however, this did not affect the amino acid sequence of the enzyme. Western blot analysis determined that animals with high concentrations of 5α-androstenone in fat and low SULT2A1 activity had corresponding low levels of SULT2A1 protein compared with animals with low levels of 5α-androstenone in fat. Real-time PCR analysis indicated that Sult2A1 mRNA was increased 2.8-fold in animals with high levels of the protein relative to animals with low levels of the protein. Furthermore, we demonstrated the positive role of the nuclear receptors constitutive androstane receptor and pregnane X receptor, as well as the possible role of farnesoid X receptor in the regulation of testicular SULT2A1 activity. Together, the results of this study suggest that differences in SULT2A1 expression can influence 5α-androstenone accumulation in fat.

scholarly journals Complementary Roles of Farnesoid X Receptor, Pregnane X Receptor, and Constitutive Androstane Receptor in Protection against Bile Acid Toxicity

2003 ◽  
Vol 278 (46) ◽  
pp. 45062-45071 ◽  
Author(s):  
Grace L. Guo ◽  
Gilles Lambert ◽  
Masahiko Negishi ◽  
Jerrold M. Ward ◽  
H. Bryan Brewer ◽  
...  
Keyword(s):  
Bile Acid ◽  
Constitutive Androstane Receptor ◽  
Pregnane X Receptor ◽  
Farnesoid X Receptor ◽  
Acid Toxicity

scholarly journals AN UNUSUAL CASE OF BENIGN RECURRENT INTRAHEPATIC CHOLESTASIS

2021 ◽  
pp. 1-2
Author(s):  
Divya Shanagonda ◽  
Srinivasan Ramadurai ◽  
G Sowmya ◽  
Preetam Arthur
Keyword(s):  
Liver Injury ◽  
Complete Remission ◽  
Plasma Exchange ◽  
Intrahepatic Cholestasis ◽  
Unusual Case ◽  
Genetic Disorder ◽  
Significant Morbidity ◽  
Progressive Familial Intrahepatic Cholestasis ◽  
Rare Genetic Disorder ◽  
Benign Recurrent Intrahepatic Cholestasis

Benign intrahepatic cholestasis (BRIC) is a rare genetic disorder characterized by episodic cholestasis. Each episode is characterized by repeated episodes of jaundice, intense pruritis last for weeks to months with complete remission. Although each episode is associated with significant morbidity, progressive liver injury and cirrhosis do not occur. In recent studies, few patients progressed to Progressive familial intrahepatic cholestasis. Here we report a case of 19 years boy with benign intrahepatic cholestasis due to an undulant course terminated by plasma exchange.

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