Bile acids are physiologic 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, and circadian misalignment is associated with the 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 hours/day for 5 days. Mice were sacrificed at 4-hour intervals over 24 hours. Hepatic metabolic genes were examined, and bile acid pool and lipid profiles were measured over 24 hours.
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. Chromatin immunoprecipitation assay revealed that hepatocyte nuclear factor 4α (HNF4α) and D-site binding protein (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
Even short-term circadian disruption dramatically alters hepatic clock gene expression, bile acid metabolism, and lipid homeostasis to contribute to dyslipidemia.
Keywords
Bile Acid Synthesis
Circadian Rhythm
Lipid Metabolism
Abbreviations used in this paper
BMAL1
brain and muscle Arnt-like 1
CCG
clock-controlled genes
ChIP
chromatin immunoprecipitation
CLOCK
circadian locomotor output cycles kaput
CYP7A1
cholesterol 7α-hydroxylase
DBP
D-site binding protein
HNF4α
hepatocyte nuclear factor 4α
Per
period
Rev-erbα
reverse-erythroblastosis α
RORα
retinoic acid-related orphan receptor α
Shp
small heterodimer partner
Srebp-1
sterol regulatory element-binding protein-1
ZT
Zeitgeber time
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Conflicts of interest The authors disclose no conflicts.
Funding This study was funded by the National Institutes of Health grants DK44442 and DK58379 (to J.Y.L.C.) and DK096784 (to J.M.F.).