title: Hepatocyte proliferation is the possible mechanism for the transient decrease in liver injury during steatosis stage of alcoholic liver disease.
abstract: Steatosis is a frequent pathologic stage in alcoholic liver disease (ALD). Although the mechanisms for increased susceptibility of steatotic liver to injury have been postulated, the ability of these hepatocytes to proliferate and withstand injury is unknown. There are conflicting reports on the status of hepatocyte regeneration following chronic alcohol ingestion. Hence, the objective of this study was to investigate the temporal dynamics between the pattern of liver injury and hepatocyte proliferation during the steatosis stage of ALD. Alcoholic steatosis was induced in male Sprague-Dawley rats by feeding an ethanol (EtOH)-containing Lieber-DeCarli liquid diet for a period of 5 weeks. Microvesicular steatosis was evident in H&E sections by three weeks in the EtOH-treated rats, which further developed into panlobular macrovesicular steatosis by 5 weeks. Plasma transaminase activities indicated progressive increase in liver injury peaking at 3 weeks with significant but mild decrease at 4 and 5 weeks. CYP2E1 protein and activity was significantly increased in EtOH-fed rats as measured by Western blot and pNP hydroxylation assay. PCNA analysis of liver sections indicated that EtOH-treated rats had a significantly higher number of cells in S phase of cell division at weeks 1 (3.20 +/- 0.19), 2 (7.03 +/- 0.92), and 3 (4.23 +/- 1.41) when compared to controls (1.5 +/- 0.22). NF-kappaB DNA binding and Cyclin D1 proteins increased significantly in the EtOH-treated rats corresponding with enhanced hepatic proliferation. These data suggest the transient decline in liver injury during alcoholic steatosis is due to enhanced NF-kappaB-dependent hepatocyte proliferation.
authors.affiliation: Department of Pathobiology, Texas Veterinary Medical Center, College of Veterinary Medicine, Texas A & M University, College Station, Texas 77843-4467, USA.
authors.forename: Udayan M
authors.initials: UM
authors.lastname: Apte
authors.forename: Rachel
authors.initials: R
authors.lastname: McRee
authors.forename: Shashi K
authors.initials: SK
authors.lastname: Ramaiah
mesh_terms: D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001219:Aspartate Aminotransferases / Q000097:blood; D049109:Cell Proliferation / Q000187:drug effects; D019938:Cyclin D1 / Q000378:metabolism; D019392:Cytochrome P-450 CYP2E1 / Q000378:metabolism; D004032:Diet; D004195:Disease Models, Animal; D000431:Ethanol / Q000008:administration & dosage / Q000633:toxicity; D005234:Fatty Liver / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology*; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D008099:Liver / Q000187:drug effects / Q000201:enzymology / Q000473:pathology*; D008108:Liver Diseases, Alcoholic / Q000209:etiology / Q000378:metabolism / Q000473:pathology*; D008115:Liver Regeneration / Q000187:drug effects / Q000502:physiology; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology; D016328:NF-kappa B / Q000378:metabolism; D018809:Proliferating Cell Nuclear Antigen / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D016328:NF-kappa B; D018809:Proliferating Cell Nuclear Antigen; D019938:Cyclin D1; D000431:Ethanol; D019392:Cytochrome P-450 CYP2E1; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase