glycogen and Liver-Diseases--Alcoholic

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 ( 19 , 44 ). 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.

Topics: Alcohol Drinking; Animals; ARNTL Transcription Factors; Circadian Rhythm; Disease Models, Animal; Gene Deletion; Gene Expression Regulation; Genotype; Glucose; Glycogen; Hepatocytes; Liver; Liver Diseases, Alcoholic; Male; Mice, Knockout; Phenotype; Time Factors

We used the intragastric feeding rat model for alcoholic liver disease to investigate alterations in glucose transporter isoforms GLUT 1 and GLUT 2 in response to different dietary fats and ethanol. Six groups of rats (three rats/group) were fed ethanol or dextrose with either saturated fat, corn oil, or fish (menhaden) oil. All control animals were pair fed the same diets as ethanol-fed rats except that ethanol was isocalorically replaced by dextrose. In all animals, the following were assessed: pathological changes in the liver, immunohistochemical and Western blot analysis of GLUT 1 and GLUT 2 isoforms, and glycogen distribution. The most severe pathological changes were seen in fish oil/ethanol fed rats, moderate changes were seen in the corn oil/ethanol group and no changes were observed in the dextrose-fed or saturated fat/ethanol groups. In the groups of rats showing pathological liver injury (corn oil/ethanol and fish oil/ethanol), the depletion in liver glycogen was accompanied by decreased GLUT 2 expression and increased GLUT 1 expression. A decrease in glycogen and GLUT 2 expression was also seen in the fish oil/dextrose-fed rats. We hypothesize that the shift in glucose transporters from GLUT 2 to GLUT 1 probably reflects a compensatory response to attenuated gluconeogenic activity and to meet the increased intracellular demand for glucose. This demand for glucose in the presence of depleted glycogen may serve to provide a source for ATP synthesis in the centrilobular zone where hypoxia occurs secondary to ethanol metabolism.

Topics: Animals; Corn Oil; Dietary Fats; Disease Models, Animal; Ethanol; Fish Oils; Glycogen; Liver; Liver Diseases, Alcoholic; Male; Monosaccharide Transport Proteins; Rats; Rats, Wistar