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 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.
Highlights
We studied the effects of cytochrome P450 (CYP)3A deficiency on the mRNA expression of genes encoding regulators of hepatic cholesterol levels using Cyp3aknockout (Cyp3a؊/؊) mice
We measured the mRNA levels of HMG-CoA synthase 1 (HMGCS1), HMG-CoA reductase (HMGCR), and squalene epoxidase (SQLE) in the livers of WT and Cyp3aϪ/Ϫ mice in order to investigate the effects of CYP3A deficiency on mRNA expression of enzymes involved in cholesterol biosynthesis
We showed for the first time that mRNA expression levels of enzymes (i.e., HMGCS1 and SQLE) involved in cholesterol biosynthesis were higher in the livers of Cyp3aϪ/Ϫ mice than in the livers of WT mice (Fig. 1)
Summary
We studied the effects of cytochrome P450 (CYP)3A deficiency on the mRNA expression of genes encoding regulators of hepatic cholesterol levels using Cyp3aknockout (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 higher in the livers of Cyp3a؊/؊ mice. Binding of SREBP-2 to the Hmgcs 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. The mRNA expression levels of genes encoding enzymes involved in bile acid synthesis, plasma levels of 7␣-hydroxy-4-cholesten-3-one and hepatic levels of total bile acid were significantly higher in Cyp3a؊/؊ mice than in WT mice.
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