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

Abstract

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 7 β -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. -Hashimoto, M., K. Kobayashi, M. Watanabe, Y. Kazuki, S. Takehara, A. Inaba, S-i. Nitta, N. Senda, M. Oshimura, and K. Chiba. Knockout of mouse Cyp3a gene enhances synthesis of cholesterol and bile acid in the liver. Copyright © 2013 by the American Society for Biochemistry and Molecular Biology, Inc.