Intestinal CYP3A4 protects against lithocholic acid-induced hepatotoxicity in intestine-specific VDR-deficient mice

Jie Cheng,Zhong-Ze Fang,Jung-Hwan Kim,Kristopher W Krausz,Naoki Tanaka,Johny.L Chiang,Frank J Gonzalez

doi:10.1194/jlr.m044420

Jie Cheng, Zhong-Ze Fang + Show 5 more

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https://doi.org/10.1194/jlr.m044420

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Abstract

Vitamin D receptor (VDR) mediates vitamin D signaling involved in bone metabolism, cellular growth and differentiation, cardiovascular function, and bile acid regulation. Mice with an intestine-specific disruption of VDR (Vdr(ΔIEpC)) have abnormal body size, colon structure, and imbalance of bile acid metabolism. Lithocholic acid (LCA), a secondary bile acid that activates VDR, is among the most toxic of the bile acids that when overaccumulated in the liver causes hepatotoxicity. Because cytochrome P450 3A4 (CYP3A4) is a target gene of VDR-involved bile acid metabolism, the role of CYP3A4 in VDR biology and bile acid metabolism was investigated. The CYP3A4 gene was inserted into Vdr(ΔIEpC) mice to produce the Vdr(ΔIEpC)/3A4 line. LCA was administered to control, transgenic-CYP3A4, Vdr(ΔIEpC), and Vdr(ΔIEpC)/3A4 mice, and hepatic toxicity and bile acid levels in the liver, intestine, bile, and urine were measured. VDR deficiency in the intestine of the Vdr(ΔIEpC) mice exacerbates LCA-induced hepatotoxicity manifested by increased necrosis and inflammation, due in part to over-accumulation of hepatic bile acids including taurocholic acid and taurodeoxycholic acid. Intestinal expression of CYP3A4 in the Vdr(ΔIEpC)/3A4 mouse line reduces LCA-induced hepatotoxicity through elevation of LCA metabolism and detoxification, and suppression of bile acid transporter expression in the small intestine. This study reveals that intestinal CYP3A4 protects against LCA hepatotoxicity.

Highlights

Vitamin D receptor (VDR) mediates vitamin D signaling involved in bone metabolism, cellular growth and differentiation, cardiovascular function, and bile acid regulation
To investigate bile acid metabolism in Vdr⌬IEpC/3A4 mice, Lithocholic acid (LCA) was administered for 4 days
Liver injury was lower in Tg3A4 mice compared with WT mice, and markedly reduced in Vdr⌬IEpC/3A4 mice compared with Vdr⌬IEpC mice as demonstrated by the reduced severity of lesion score (P < 0.05), coagulation necrosis (P < 0.05), biliary proliferation, inflammation cell infiltration, and portal inflammation Hepatotoxicity was most severe in Vdr⌬IEpC mice compared with WT mice, and Vdr⌬IEpC/3A4 mice compared with Tg-3A4 mice

Summary

Introduction

Vitamin D receptor (VDR) mediates vitamin D signaling involved in bone metabolism, cellular growth and differentiation, cardiovascular function, and bile acid regulation. Mice with an intestine-specific disruption of VDR (Vdr⌬IEpC) have abnormal body size, colon structure, and imbalance of bile acid metabolism. LCA was administered to control, transgenic-CYP3A4, Vdr⌬IEpC, and Vdr⌬IEpC/3A4 mice, and hepatic toxicity and bile acid levels in the liver, intestine, bile, and urine were measured. VDR deficiency in the intestine of the Vdr⌬IEpC mice exacerbates LCA-induced hepatotoxicity manifested by increased necrosis and inflammation, due in part to over-accumulation of hepatic bile acids including taurocholic acid and taurodeoxycholic acid. Intestinal expression of CYP3A4 in the Vdr⌬IEpC/3A4 mouse line reduces LCA-induced hepatotoxicity through elevation of LCA metabolism and detoxification, and suppression of bile acid transporter expression in the small intestine. Intestinal CYP3A4 protects against lithocholic acid-induced hepatotoxicity in intestine-specific VDR-deficient mice. VDR might play a crucial role in regulation of bile acid metabolism [13]

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