Short-Term Circadian Disruption Impairs Bile Acid and Lipid Homeostasis in Mice

BACKGROUND & AIMS Bile acids are physiological detergents that also activate nuclear receptors to regulate glucose and lipid homeostasis. Cholesterol 7α-hydroxylase (Cyp7a1), the rate-limiting enzyme that converts cholesterol to bile acids, is transcriptionally regulated by bile acids and circadian rhythms. Fasting, nutrients and the circadian clock critically control hepatic bile acid and lipid homeostasis, while circadian misalignment is associated with metabolic syndrome in humans. To delineate these interactions, we employed a sleep disruption model to induce circadian disruption and examined hepatic metabolism with respect to bile acids, lipids and clock gene expression. METHODS B6xC57 mice were maintained on chow or Western diet and were sleep disrupted for 6 hr/day for 5 days. Mice were sacrificed at 4 hr intervals over 24 hr. Hepatic metabolic genes were examined, and bile acid pool and lipid profiles were measured over 24 hr. RESULTS Sleep disruption significantly suppressed circadian expression of core clock genes, genes involved in lipid metabolism, and key regulators of Cyp7a1 as well as Cyp7a1 expression itself. Sleep disruption abolished the peak in serum cholesterol and increased liver and serum free fatty acids. Bile acid pool size was increased while liver bile acids were decreased. ChIP assay revealed HNF4α and Dbp occupancies were suppressed at the Cyp7a1 promoter in sleep-disrupted mice. When coupled with Western diet, sleep disruption abolished liver clock rhythms and elevated free fatty acids. CONCLUSIONS This study suggests that even short-term circadian disruption dramatically alters hepatic clock gene expression, bile acid metabolism and lipid homeostasis to contribute to dyslipidemia.