Circadian rhythm disturbances are associated with metabolic syndrome and obesity in humans, leading to altered homeostatic regulation of glucose, insulin, and lipids. Bile acids are physiological detergents essential for the transport and absorption of nutrients and metabolites, and also act as nuclear receptor substrates in the cell signaling pathways that modulate lipid and glucose energy metabolism and homeostasis. Transcriptional activity of cholesterol 7?-hydroxylase (CYP7A1), the rate-limiting enzyme in the conversion of cholesterol to bile acids, is strictly regulated by components of the cellular environment, including bile acids, nutrient availability, insulin, and other factors. Recent studie also indicate that CYP7A1 displays a diurnal rhythm of expression in rodents and humans, and this rhythm is shifted under conditions of altered diet and time of feeding, leading to disturbed regulation of bile acid homeostasis and metabolism. The proposed experiments will further examine the interactions of circadian rhythms and hepatic metabolism in a CYP7A1 humanized mouse model undergoing sleep deprivation and high-fat feeding to elucidate the mechanisms by which circadian misregulation contributes to Type II diabetes and obesity in humans.
Bile acids are critical for maintaining energy homeostasis through glucose and lipid metabolism via circadian regulation of the human CYP7A1 gene. Diabetes, obesity, and metabolic syndrome are associated with perturbations in circadian rhythms due to jet lag, shift work, and sleep deprivation, while altered diet composition can affect peripheral rhythmic gene expression. The proposed studies aim to understand the contribution of deregulated circadian liver metabolism in the progression of diabetes and obesity.
|Ferrell, Jessica M; Boehme, Shannon; Li, Feng et al. (2016) Cholesterol 7?-hydroxylase-deficient mice are protected from high-fat/high-cholesterol diet-induced metabolic disorders. J Lipid Res 57:1144-54|
|Ferrell, Jessica M; Chiang, John Y L (2015) Short-term circadian disruption impairs bile acid and lipid homeostasis in mice. Cell Mol Gastroenterol Hepatol 1:664-677|
|Ferrell, Jessica M; Chiang, John Y L (2015) Circadian rhythms in liver metabolism and disease. Acta Pharm Sin B 5:113-22|
|Li, Tiangang; Francl, Jessica M; Boehme, Shannon et al. (2013) Regulation of cholesterol and bile acid homeostasis by the cholesterol 7?-hydroxylase/steroid response element-binding protein 2/microRNA-33a axis in mice. Hepatology 58:1111-21|