title: 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 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.
authors.affiliation: Laboratory of Pharmacology and Toxicology, Graduate School of Pharmaceutical Sciences, Chiba University, Chiba 260-8675, Japan.
authors.forename: Mari
authors.initials: M
authors.lastname: Hashimoto
authors.affiliation: Laboratory of Pharmacology and Toxicology, Graduate School of Pharmaceutical Sciences, Chiba University, Chiba 260-8675, Japan.
authors.forename: Kaoru
authors.initials: K
authors.lastname: Kobayashi
authors.affiliation: Laboratory of Pharmacology and Toxicology, Graduate School of Pharmaceutical Sciences, Chiba University, Chiba 260-8675, Japan.
authors.forename: Mio
authors.initials: M
authors.lastname: Watanabe
authors.affiliation: Department of Biomedical Science, Institute of Regenerative Medicine and Biofunction, Graduate School of Medical Science, Tottori University, Tottori 683-8503, Japan; Chromosome Engineering Research Center (CERC), Tottori University, Tottori 683-8503, Japan.
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Kazuki
authors.affiliation: Chromosome Engineering Research Center (CERC), Tottori University, Tottori 683-8503, Japan.
authors.forename: Shoko
authors.initials: S
authors.lastname: Takehara
authors.affiliation: Laboratory of Pharmacology and Toxicology, Graduate School of Pharmaceutical Sciences, Chiba University, Chiba 260-8675, Japan.
authors.forename: Asumi
authors.initials: A
authors.lastname: Inaba
authors.affiliation: Laboratory of Pharmacology and Toxicology, Graduate School of Pharmaceutical Sciences, Chiba University, Chiba 260-8675, Japan; Mitsubishi Chemical Medience Corporation, Ibaraki 305-0047, Japan.
authors.forename: Shin-Ichiro
authors.initials: SI
authors.lastname: Nitta
authors.affiliation: Mitsubishi Chemical Medience Corporation, Ibaraki 305-0047, Japan.
authors.forename: Naoto
authors.initials: N
authors.lastname: Senda
authors.affiliation: Department of Biomedical Science, Institute of Regenerative Medicine and Biofunction, Graduate School of Medical Science, Tottori University, Tottori 683-8503, Japan; Chromosome Engineering Research Center (CERC), Tottori University, Tottori 683-8503, Japan.
authors.forename: Mitsuo
authors.initials: M
authors.lastname: Oshimura
authors.affiliation: Laboratory of Pharmacology and Toxicology, Graduate School of Pharmaceutical Sciences, Chiba University, Chiba 260-8675, Japan.
authors.forename: Kan
authors.initials: K
authors.lastname: Chiba
mesh_terms: D000818:Animals; D001647:Bile Acids and Salts / Q000096:biosynthesis*; D002784:Cholesterol / Q000096:biosynthesis*; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D008099:Liver / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D008565:Membrane Proteins
chemical_list: D001647:Bile Acids and Salts; D002784:Cholesterol; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System; D012333:RNA, Messenger; C496508:Cyp3a11 protein, mouse; D008565:Membrane Proteins
keywords: 25-hydroxy-cholesterol; HMG-CoA synthase 1; cytochrome P450 3A; squalene epoxidase; sterol regulatory element-binding protein-2