Effects of Ethanol Administration on Components of the Ubiquitin Proteolytic Pathway in Rat Liver

Abstract

creased catabolism of ubiquitin and its conjugates. Our Hepatic protein accumulation during ethanol adminfindings also provide no indication that the ethanol-elicistration may result partly from an ethanol-elicited deited reduction in hepatic proteolysis is because of a ubicline in hepatic protein degradation, which we have prequitin-mediated mechanism. (HEPATOLOGY 1996;23:1556-viously shown. We conducted the current studies to 1563.) examine the effects of ethanol administration on the levels of hepatic ubiquitin, an 8.5-kd protein which is an important mediator of extralysosomal protein cataboHepatomegaly is common in alcoholics and alcohollism. Rats were pair-fed liquid diets containing either fed experimental animals. It is closely associated with ethanol (36% of calories) or isocaloric maltose-dextrin increased levels of heptocellular protein that contribute for 1 to 5 weeks. Ubiquitin was immunochemically quan-to hepatocyte hypertrophy. Ubiquitin is found in all eukaryotic cells. It is a tin conjugating activity of crude and diethyl aminoethyl-fractionated liver cytosols of ethanol-fed rats had highly conserved 76-amino acid protein (relative molecequal capacities to those from controls in catalyzing the ular mass Å 8.5 kd) that covalently binds proteins desformation of ubiquitin-protein conjugates. Our findings tined for degradation. Three enzymes, E1, E2, and E3, indicate that chronic ethanol consumption increased catalyze the formation of ubiquitin-protein conjugates, the level of immunoreactive ubiquitin in rat liver. This a process called ubiquitylation (for reviews, see refermay have resulted from enhanced ubiquitin production ences 12-14). Cellular proteins targeted for degradation because of an ethanol-elicited stress response and/or de-are ubiquitylated at their NH 2 termini and at the eamino groups of lysine residues within the polypeptide chain. These conjugation points may each carry one substrate and recycles intact ubiquitin for further Received March 11, 1994; accepted January 12, 1996. rounds of ubiquitylation. 17Current address of Dr. Born is Indiana University Medical Center, 975The apparent role of the ubiquitin-mediated proteo-

Peptidase activities of the multicatalytic protease in rat liver after voluntary and intragastric ethanol administration

“…However, the tendency for the Cht-L and PGPH activities to be numerically higher in livers of ethanol-fed rats ( Table 2) was intriguing in view of our previous work that demonstrated a rise in hepatic ubiquitin, after voluntary alcohol consumption. 23 Grune et al also reported a small increase in the Cht-L activity in liver epithelial cells exposed to severe oxidative stress. 12 Taken together, the data would suggest that voluntary ethanol administration causes subtle changes in the proteasome that enhance specific peptidase activities.…”

“…[19][20][21][22] Our laboratory previously reported that the levels of immunoreactive ubiquitin in hepatocytes from rats fed the Lieber-DeCarli ethanol diet are higher than those from pair-fed control animals. 23 These findings prompted us to examine whether similar changes occur in the activity and content of the proteasome in livers of rats subjected to chronic ethanol administration. Here, we examined the peptidase activities of the enzyme in rats pair-fed control and ethanol liquid diets (voluntary feeding), as well as those from animals fed similar liquid diets by continuous intragastric feeding.…”

Effect of copper intoxication on rat liver proteasome activity: Relationship with oxidative stress

“…Reinheckel et al [30] show that the activity of proteasomes toward the LLVY-AMC is inhibited when they are exposed to H 2 O 2 , peroxynitrite, and hypochlorite. Other oxidative stressors, such as ethanol [31], dopamine [32], cadmium [33], as well as physiologic and pathologic states, associated with OS (aging, degenerative diseases, and ischemia/reperfusion), have exerted the same effect. However, the exact nature of copper-induced decline in proteasome peptidase activities is still unclear.…”

Effects of Chronic Ethanol Administration on Rat Liver Proteasome Activities: Relationship With Oxidative Stress

“…15,16 It has been also reported that ethanol administration, using the Lieber-DeCarli model, elicited a rise in hepatocellular ubiquitin level, a crucial component of the extralysosomal proteolytic pathway. 17 Whether such an accumulation of ubiquitin and ubiquitin protein conjugates results from a decrease in the proteasome pathway has not yet been investigated. Moreover, long-term ethanol consumption is associated with varying degrees of oxidative stress, according to the method of ethanol administration.…”