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

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.

• Authors: Jie Cheng, Zhong-Ze Fang, Jung-Hwan Kim, Kristopher W Krausz, Naoki Tanaka, John Y L Chiang, Frank J Gonzalez
• Journal: Journal of lipid research (J Lipid Res) Vol. 55 Issue 3 Pg. 455-65 (Mar 2014) ISSN: 1539-7262 [Electronic] United States
• PMID: 24343899 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Bile Acids and Salts
• Receptors, Calcitriol
• Lithocholic Acid
• Cholesterol
• Cytochrome P-450 CYP3A
• cytochrome P450 3A4, mouse

Topics

• Animals
• Bile (metabolism)
• Bile Acids and Salts (metabolism)
• Blotting, Western
• Chemical and Drug Induced Liver Injury (etiology, genetics, metabolism)
• Cholesterol (blood, metabolism)
• Cytochrome P-450 CYP3A (genetics, metabolism, urine)
• Gallbladder (metabolism)
• Intestinal Mucosa (metabolism)
• Lithocholic Acid
• Liver (metabolism, pathology)
• Male
• Metabolomics (methods)
• Mice
• Mice, Knockout
• Mice, Transgenic
• Receptors, Calcitriol (deficiency, genetics)
• Reverse Transcriptase Polymerase Chain Reaction