Effects of Absence of Constitutive Androstane Receptor (CAR) on Bile Acid Homeostasis in Male and Female Mice.

Document Type

Article

Publication Date

9-2019

Identifier

DOI: 10.1093/toxsci/kfz143; PMCID: PMC6735724

Abstract

Accumulation of BAs in hepatocytes has a role in liver disease and also in drug-induced liver injury. The Constitutive Androstane Receptor (CAR) has been shown to protect against BA-induced liver injury. The polymorphism of CAR has recently been shown to modify the pharmacokinetics and pharmacodynamics of various drugs. Thus it was hypothesized that polymorphism of CAR may also influence BA homeostasis. Using CAR-null and WT mice, this study modeled the potential consequences of CAR polymorphism on BA homeostasis. Our previous study showed that chemical activation of CAR decreases the total BA concentrations in livers of mice. Surprisingly the absence of CAR also decreased the BA concentrations in livers of mice, but to a lesser extent than in CAR-activated mice. Neither CAR activation nor elimination of CAR altered the biliary excretion of total BAs, but CAR activation increased the proportion of 6-OH BAs (TMCA), whereas the lack of CAR increased the excretion of TCA, TCDCA and TDCA. Serum BA concentrations did not parallel the decrease in BA concentrations in the liver in either the mice after CAR activation or mice lacking CAR. Gene expression of BA synthesis, transporter and regulator genes were mainly similar in livers of CAR-null and WT mice. In summary, CAR activation decreases primarily the 12-OH BA concentrations in liver, whereas lack of CAR decreases the concentrations of 6-OH BAs in liver. In bile, CAR activation increases the biliary excretion of 6-OH BAs, whereas absence of CAR increases the biliary excretion of 12-OH BAs and TCDCA.

Journal Title

Toxicological sciences : an official journal of the Society of Toxicology

Volume

171

Issue

1

First Page

132

Last Page

145

Keywords

Constitutive Androstane Receptor; bile acids; biliary excretion; muricholic acid; taurocholic acid

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