Liver and Biliary Tract Physiology/Pathophysiology: Genetic deletion of the circadian clock transcription factor BMAL1 and chronic alcohol consumption differentially alter hepatic glycogen in mice

摘要

Multiple metabolic pathways exhibit time-of-day-dependent rhythms that are controlled by the molecular circadian clock. We have shown that chronic alcohol is capable of altering the molecular clock and diurnal oscillations in several elements of hepatic glycogen metabolism (, ). Herein, we sought to determine whether genetic disruption of the hepatocyte clock differentially impacts hepatic glycogen content in chronic alcohol-fed mice. Male hepatocyte-specific BMAL1 knockout (HBK) and littermate controls were fed control or alcohol-containing diets for 5 wk to alter hepatic glycogen content. Glycogen displayed a significant diurnal rhythm in livers of control genotype mice fed the control diet. While rhythmic, alcohol significantly altered the diurnal oscillation of glycogen in livers of control genotype mice. The glycogen rhythm was mildly altered in livers of control-fed HBK mice. Importantly, glycogen content was arrhythmic in livers of alcohol-fed HBK mice. Consistent with these changes in hepatic glycogen content, we observed that some glycogen and glucose metabolism genes were differentially altered by chronic alcohol consumption in livers of HBK and littermate control mice. Diurnal rhythms in glycogen synthase (mRNA and protein) were significantly altered by alcohol feeding and clock disruption. Alcohol consumption significantly altered Gck, Glut2, and Ppp1r3g rhythms in livers of control genotype mice, with diurnal rhythms of Pklr, Glut2, Ppp1r3c, and Ppp1r3g further disrupted (dampened or arrhythmic) in livers of HBK mice. Taken together, these findings show that chronic alcohol consumption and hepatocyte clock disruption differentially influence the diurnal rhythm of glycogen and various key glycogen metabolism-related genes in the liver.>NEW & NOTEWORTHY We report that circadian clock disruption exacerbates alcohol-mediated alterations in hepatic glycogen. We observed differential responsiveness in diurnal rhythms of glycogen and glycogen metabolism genes and proteins in livers of hepatocyte-specific BMAL1 knockout and littermate control mice fed alcohol. Our findings provide new insights into potential mechanisms by which alcohol alters glycogen, an important energy source for liver and other organs.