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Multiple Mechanisms Regulate Circadian Expression of the Gene for Cholesterol 7-Hydroxylase (Cyp7a), a Key Enzyme in Hepatic Bile Acid Biosynthesis

Department of Dental and Medical Biochemistry, Hiroshima University Graduate School of Biomedical Sciences, Hiroshima, noshiro{at}hiroshima-u.ac.jp

Emiko Usui

Department of Dental and Medical Biochemistry, Hiroshima University Graduate School of Biomedical Sciences, Hiroshima

Takeshi Kawamoto

Department of Dental and Medical Biochemistry, Hiroshima University Graduate School of Biomedical Sciences, Hiroshima

Hiroshi Kubo

Department of Dental and Medical Biochemistry, Hiroshima University Graduate School of Biomedical Sciences, Hiroshima

Katsumi Fujimoto

Department of Dental and Medical Biochemistry, Hiroshima University Graduate School of Biomedical Sciences, Hiroshima

Masae Furukawa

Department of Prosthetic Dentistry, Hiroshima University Graduate School of Biomedical Sciences, Hiroshima

Sato Honma

Department of Physiology, Hokkaido University Graduate School of Medicine, Sapporo

Makoto Makishima

Department of Biochemistry, Nihon University School of Medicine, Tokyo, Japan

Ken-ichi Honma

Department of Physiology, Hokkaido University Graduate School of Medicine, Sapporo

Yukio Kato

Department of Dental and Medical Biochemistry, Hiroshima University Graduate School of Biomedical Sciences, Hiroshima

Cholesterol 7-hydroxylase (CYP7A) and sterol 12-hydroxylase (CYP8B) in bile acid biosynthesis and 3-hydroxyl-3-methylglutaryl CoA reductase (HMGCR) in cholesterol biosynthesis are the key enzymes in hepatic metabolic pathways, and their transcripts exhibit circadian expression profiles in rodent liver. The authors determined transcript levels of these enzymes and the regulatory factors for Cyp7a—including Dbp, Dec2, E4bp4, Hnf4, Ppar, Lxr, Rev-erb, and Rev-erbß—in the liver of wild-type and homozygous Clock mutant mice (Clock/Clock) and examined the effects of these transcription factors on the transcription activities of Cyp7a. The expression profile of the Cyp7a transcript in wild-type mice showed a strong circadian rhythm in both the 12L:12D light-dark cycle and constant darkness, and that in Clock/Clock also exhibited a circadian rhythm at an enhanced level with a lower amplitude, although its protein level became arrhythmic at a high level. The expression profile of Cyp8b mRNA in wild-type mice showed a shifted circadian rhythm from that of Cyp7a, becoming arrhythmic in Clock/Clock at an expression level comparable to that of wild-type mice. The expression profile of Hmgcr mRNA also lost its strong circadian rhythm in Clock/Clock , showing an expression level comparable to that of wild-type mice. The expressions of Dbp, Dec2, Rev-erb, and Rev-erb ß—potent regulators for Cyp7a expression—were abolished or became arrhythmic in Clock/Clock, while other regulators for Cyp7a—Lxr, Hnf4, Ppar, and E4bp4—had either less affected or enhanced expression in Clock/Clock. In luciferase reporter assays, REV-ERB/ß, DBP, LXR, and HNF4 increased the promoter activity of Cyp7a, whereas DEC2 abolished the transcription from the Cyp7a promoter: E4BP4 and PPAR were moderate negative regulators. Furthermore, knockdown of REV-ERB/ß with siRNA suppressed Cyp7a transcript levels, and in the electrophoretic mobility shift assay, REV-ERB/ß bound to the promoter of Cyp7a . These observations suggest that (1) active CLOCK is essential for the robust circadian expression of hepatic metabolic enzymes (Cyp7a, Cyp8b, and Hmgcr); (2) clock-controlled genes—DBP, DEC2, and REV-ERB/ß—are direct regulators required for the robust circadian rhythm of Cyp7a; and (3) the circadian rhythm of Cyp7a is regulated by multiple transcription factors, including DBP, REV-ERB/ß, LXR, HNF4 DEC2, E4BP4, and PPAR.

Key Words: CLOCK • CYP7A • CYP8B • HMGCR • DEC2 • DBP • REV-ERB • LXR

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