title: Clock mutation facilitates accumulation of cholesterol in the liver of mice fed a cholesterol and/or cholic acid diet.
abstract: Cholesterol (CH) homeostasis in the liver is regulated by enzymes of CH synthesis such as 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR) and catabolic enzymes such as cytochrome P-450, family 7, subfamily A, and polypeptide 1 (CYP7A1). Since a circadian clock controls the gene expression of these enzymes, these genes exhibit circadian rhythm in the liver. In this study, we examined the relationship between a diet containing CH and/or cholic acid (CA) and the circadian regulation of Hmgcr, low-density lipoprotein receptor (Ldlr), and Cyp7a1 gene expression in the mouse liver. A 4-wk CA diet lowered and eventually abolished the circadian expression of these genes. Not only clock genes such as period homolog 2 (Drosophila) (Per2) and brain and muscle arnt-like protein-1 (Bmal1) but also clock-controlled genes such as Hmgcr, Ldlr, and Cyp7a1 showed a reduced and arrhythmic expression pattern in the liver of Clock mutant mice. The reduced gene expression of Cyp7a1 in mice fed a diet containing CA or CH + CA was remarkable in the liver of Clock mutants compared with wild-type mice, and high liver CH accumulation was apparent in Clock mutant mice. In contrast, a CH diet without CA only elevated Cyp7a1 expression in both wild-type and Clock mutant mice. The present findings indicate that normal circadian clock function is important for the regulation of CH homeostasis in the mouse liver, especially in conjunction with a diet containing high CH and CA.
authors.affiliation: Dept. of Physiology and Pharmacology, School of Science and Engineering, Waseda University, Higashifushimi 2-7-5, Nishitokyo-Shi, Tokyo 202-0021, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Kudo
authors.forename: Mihoko
authors.initials: M
authors.lastname: Kawashima
authors.forename: Toru
authors.initials: T
authors.lastname: Tamagawa
authors.forename: Shigenobu
authors.initials: S
authors.lastname: Shibata
mesh_terms: D056930:ARNTL Transcription Factors; D000214:Acyl Coenzyme A / Q000235:genetics; D000821:Animal Feed; D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics; D001921:Brain / Q000502:physiology; D056926:CLOCK Proteins; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism; D002790:Cholesterol 7-alpha-Hydroxylase / Q000235:genetics / Q000378:metabolism; D002791:Cholesterol, Dietary / Q000097:blood / Q000493:pharmacokinetics*; D019826:Cholic Acid / Q000493:pharmacokinetics*; D002940:Circadian Rhythm / Q000502:physiology*; D004268:DNA-Binding Proteins / Q000235:genetics; D015870:Gene Expression / Q000502:physiology; D006706:Homeostasis / Q000502:physiology; D008099:Liver / Q000378:metabolism*; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D008817:Mice, Mutant Strains; D018482:Muscle, Skeletal / Q000502:physiology; D009154:Mutation; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D056950:Period Circadian Proteins; D011973:Receptors, LDL / Q000235:genetics; D051782:Sterol Regulatory Element Binding Protein 2 / Q000235:genetics; D015534:Trans-Activators / Q000235:genetics* / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism
chemical_list: D056930:ARNTL Transcription Factors; D000214:Acyl Coenzyme A; D051792:Basic Helix-Loop-Helix Proteins; D056926:CLOCK Proteins; D018797:Cell Cycle Proteins; D002790:Cholesterol 7-alpha-Hydroxylase; D002791:Cholesterol, Dietary; D019826:Cholic Acid; D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; D056950:Period Circadian Proteins; D011973:Receptors, LDL; D051782:Sterol Regulatory Element Binding Protein 2; D015534:Trans-Activators; D014157:Transcription Factors; C538961:Bmal1 protein, mouse; C498260:Dbp protein, mouse; C513312:Per2 protein, mouse; C497391:Srebf2 protein, mouse; C008047:3-hydroxy-3-methylglutaryl-coenzyme A; C502772:Cyp7a1 protein, mouse; C538944:Clock protein, mouse