Chronic ethanol consumption disrupts diurnal rhythms of hepatic glycogen metabolism in mice

Abstract

Chronic ethanol consumption has been shown to significantly decrease hepatic glycogen content; however, the mechanisms responsible for this adverse metabolic effect are unknown. In this study, we examined the impact chronic ethanol consumption has on time-of-day-dependent oscillations (rhythms) in glycogen metabolism processes in the liver. For this, male C57BL/6J mice were fed either a control or ethanol-containing liquid diet for 5 wk, and livers were collected every 4 h for 24 h and analyzed for changes in various genes and proteins involved in hepatic glycogen metabolism. Glycogen displayed a robust diurnal rhythm in the livers of mice fed the control diet, with the peak occurring during the active (dark) period of the day. The diurnal glycogen rhythm was significantly altered in livers of ethanol-fed mice, with the glycogen peak shifted into the inactive (light) period and the overall content of glycogen decreased compared with controls. Chronic ethanol consumption further disrupted diurnal rhythms in gene expression (glycogen synthase 1 and 2, glycogenin, glucokinase, protein targeting to glycogen, and pyruvate kinase), total and phosphorylated glycogen synthase protein, and enzyme activities of glycogen synthase and glycogen phosphorylase, the rate-limiting enzymes of glycogen metabolism. In summary, these results show for the first time that chronic ethanol consumption disrupts diurnal rhythms in hepatic glycogen metabolism at the gene and protein level. Chronic ethanol-induced disruption in these daily rhythms likely contributes to glycogen depletion and disruption of hepatic energy homeostasis, a recognized risk factor in the etiology of alcoholic liver disease.

Diurnal Oscillations in Liver Mass and Cell Size Accompany Ribosome Assembly Cycles

“…Glycogen levels vary in a daily fashion, but in ad-lib-fed mice, they only contribute about 4% and 6.5% to liver weight at trough and peak levels, respectively (Udoh et al, 2015). Therefore, they cannot account for the 34% difference in liver mass reported above.…”

Circadian Rhythms in Gastrointestinal Health and Diseases

“…This desynchronization can mediate alcohol’s effects on hepatic lipid, glycogen, and mitochondrial metabolism. Her findings suggest a regulatory role for the liver clock on alcohol-induced liver injury and glycogen depletion 15 . In a hepatocyte-specific BMAL1 knockout mouse model for alcoholic fatty liver disease, failures in clock-driven metabolic adaptive processes in the alcohol-exposed liver mediated alcohol-induced hepatic bioenergetic stress and liver injury.…”

Inhibition of expression of the circadian clock gene Period causes metabolic abnormalities including repression of glycometabolism in Bombyx mori cells

“…Changes in the alcohol metabolic pathway were observed in a Drosophila Per mutant, resulting in differences in alcohol tolerance and clearance capability64. On the other hand, long-term alcohol intake in mice can lead to changes in the circadian rhythm65, whilst damaging the normal rhythm of liver glycogen metabolism66. Numerous studies have reported such reciprocal regulation of the circadian clock by metabolites, whereby the metabolites regulate expression of core circadian clock genes, thus changing the circadian rhythm.…”