Knockout of mouse Cyp3a gene enhances synthesis of cholesterol and bile acid in the liver

• Published in: Journal of lipid research Vol. 54; no. 8; pp. 2060 - 2068
• Main Authors: Hashimoto, Mari, Kobayashi, Kaoru, Watanabe, Mio, Kazuki, Yasuhiro, Takehara, Shoko, Inaba, Asumi, Nitta, Shin-ichiro, Senda, Naoto, Oshimura, Mitsuo, Chiba, Kan
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.08.2013; The American Society for Biochemistry and Molecular Biology; Elsevier
• Subjects: 25-hydroxy-cholesterol; Animals; Bile Acids and Salts - biosynthesis; Cholesterol - biosynthesis; Cytochrome P-450 CYP3A; Cytochrome P-450 Enzyme System - deficiency; Cytochrome P-450 Enzyme System - genetics; Cytochrome P-450 Enzyme System - metabolism; cytochrome P450 3A; HMG-CoA synthase 1; Liver - metabolism; Mice; Mice, Inbred C57BL; RNA, Messenger - genetics; RNA, Messenger - metabolism; squalene epoxidase; sterol regulatory element-binding protein-2; squalene epoxidase; cytochrome P450 3A; sterol regulatory element-binding protein-2; 25-hydroxy-cholesterol; HMG-CoA synthase 1
• ISSN: 0022-2275; 1539-7262
• DOI: 10.1194/jlr.M033464

Here, we studied the effects of cytochrome P450 (CYP)3A deficiency on the mRNA expression of genes encoding regulators of hepatic cholesterol levels using Cyp3a-knockout (Cyp3a−/−) mice. The mRNA expression levels of genes encoding enzymes involved in cholesterol biosynthesis in the livers of Cyp3a−/− mice were higher than those of wild-type (WT) mice. Nuclear levels of sterol regulatory element-binding protein-2 (SREBP-2), which enhances cholesterol biosynthesis, were also higher in the livers of Cyp3a−/− mice. Binding of SREBP-2 to the Hmgcs1 gene promoter was more abundant in the livers of Cyp3a−/− mice. These results suggest that deficiency of CYP3A enzymes enhances transcription of genes encoding enzymes involved in cholesterol biosynthesis via activation of SREBP-2. On the other hand, hepatic cholesterol levels in Cyp3a−/− mice were 20% lower than those in WT mice. The mRNA expression levels of genes encoding enzymes involved in bile acid synthesis, plasma levels of 7α-hydroxy-4-cholesten-3-one and hepatic levels of total bile acid were significantly higher in Cyp3a−/− mice than in WT mice. These findings suggest that reduction of hepatic total cholesterol in Cyp3a−/− mice would be the consequence of enhanced bile acid synthesis. Therefore, CYP3A enzymes appear to play roles in the synthesis of cholesterol and bile acid in vivo.