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(Circulation Research. 2009;105:545.)
© 2009 American Heart Association, Inc.

Integrative Physiology

Regular Feeding Plays an Important Role in Cholesterol Homeostasis Through the Liver Circadian Clock

Daisuke Yamajuku, Shingo Okubo, Tomonori Haruma, Takahiko Inagaki, Yuji Okuda, Tomoko Kojima, Keiji Noutomi, Seiichi Hashimoto, Hiroaki Oda

From the Department of Applied Molecular Biosciences (D.Y., S.O., T.H., T.I., Y.O., H.O.), Laboratory of Nutritional Biochemistry, Nagoya University; and Pharmacology Research Laboratories (D.Y.) and Molecular Medicine Research Laboratories (T.K., K.N., S.H.), Drug Discovery Research, Astellas Pharma Inc, Ibaraki, Japan.

Correspondence to Hiroaki Oda, Department of Applied Molecular Biosciences, Laboratory of Nutritional Biochemistry, Nagoya University, Nagoya 464-8601, Japan. E-mail hirooda{at}agr.nagoya-u.ac.jp

Rationale: Peripheral clock control and the relevance of the circadian rhythm to physiology and disease are major questions in mammalian circadian biology.

Objective: We examined the physiological functions of the liver clock.

Methods and Results: We established a suppressed feeding schedule regimen constituting a high-cholesterol diet delivered every 6 hours without changes in energy and cholesterol intake. We found that rats exposed to this regimen developed hypercholesteremia. In the liver, the rhythmicity of expression of several clock genes was disrupted. Furthermore, the nocturnal expression of the CYP7A1 gene, which encodes the rate-limiting enzyme for the conversion of cholesterol to bile acids, was shifted to a diurnal pattern. Indeed, suppression of a regular feeding rhythm increased the secretion rate of very-low-density lipoprotein cholesterol from the liver and decreased the excretion of fecal bile acids.

Conclusions: Our results demonstrated that not only the amount and quality of food but also the timing of meals has crucial health implications.

Key Words: cholesterol homeostasis • circadian rhythm • lifestyle-related diseases • metabolic syndrome