title: Experimental nonalcoholic steatohepatitis compromises ureagenesis, an essential hepatic metabolic function.
abstract: Nonalcoholic steatohepatitis (NASH) is increasing in prevalence, yet its consequences for liver function are unknown. We studied ureagenesis, an essential metabolic liver function of importance for whole body nitrogen homeostasis, in a rodent model of diet-induced NASH. Rats were fed a high-fat, high-cholesterol diet for 4 and 16 wk, resulting in early and advanced experimental NASH, respectively. We examined the urea cycle enzyme mRNAs in liver tissue, the hepatocyte urea cycle enzyme proteins, and the in vivo capacity of urea-nitrogen synthesis (CUNS). Early NASH decreased all of the urea cycle mRNAs to an average of 60% and the ornithine transcarbamylase protein to 10%, whereas the CUNS remained unchanged. Advanced NASH further decreased the carbamoyl phosphate synthetase protein to 63% and, in addition, decreased the CUNS by 20% [from 5.65 ± 0.23 to 4.58 ± 0.30 μmol × (min × 100 g)(-1); P = 0.01]. Early NASH compromised the genes and enzyme proteins involved in ureagenesis, whereas advanced NASH resulted in a functional reduction in the capacity for ureagenesis. The pattern of urea cycle perturbations suggests a prevailing mitochondrial impairment by NASH. The decrease in CUNS has consequences for the ability of the body to adjust to changes in the requirements for nitrogen homeostasis e.g., at stressful events. NASH, thus, in terms of metabolic consequences, is not an innocuous lesion, and the manifestations of the damage seem to be a continuum with increasing disease severity.
authors.affiliation: Department of Hepatology & Gastroenterology, Aarhus University Hospital, Aarhus, Denmark; karethom@rm.dk.
authors.forename: Karen Louise
authors.initials: KL
authors.lastname: Thomsen
authors.affiliation: Department of Hepatology & Gastroenterology, Aarhus University Hospital, Aarhus, Denmark;
authors.forename: Henning
authors.initials: H
authors.lastname: Grønbæk
authors.affiliation: Department of Hepatology & Gastroenterology, Aarhus University Hospital, Aarhus, Denmark;
authors.forename: Emilie
authors.initials: E
authors.lastname: Glavind
authors.affiliation: Storr Liver Unit, Westmead Millennium Institute and Westmead Hospital, University of Sydney, Westmead, Australia;
authors.forename: Lionel
authors.initials: L
authors.lastname: Hebbard
authors.affiliation: Department of Clinical Pharmacology, Aarhus University Hospital, Aarhus, Denmark; The Medical Research Laboratory, Department of Clinical Medicine, Aarhus University, Aarhus, Denmark; and.
authors.forename: Niels
authors.initials: N
authors.lastname: Jessen
authors.affiliation: Centre for Liver Disease Research, School of Medicine, University of Queensland, Brisbane, Australia.
authors.forename: Andrew
authors.initials: A
authors.lastname: Clouston
authors.affiliation: Storr Liver Unit, Westmead Millennium Institute and Westmead Hospital, University of Sydney, Westmead, Australia;
authors.forename: Jacob
authors.initials: J
authors.lastname: George
authors.affiliation: Department of Hepatology & Gastroenterology, Aarhus University Hospital, Aarhus, Denmark;
authors.forename: Hendrik
authors.initials: H
authors.lastname: Vilstrup
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000097:blood; D002222:Carbamoyl-Phosphate Synthase (Ammonia) / Q000235:genetics / Q000378:metabolism; D002791:Cholesterol, Dietary; D059305:Diet, High-Fat; D004195:Disease Models, Animal; D018450:Disease Progression; D005234:Fatty Liver / Q000139:chemically induced / Q000201:enzymology / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D005260:Female; D015971:Gene Expression Regulation, Enzymologic; D006706:Homeostasis; D008099:Liver / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D008930:Mitochondria, Liver / Q000378:metabolism; D065626:Non-alcoholic Fatty Liver Disease; D009954:Ornithine Carbamoyltransferase / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D012720:Severity of Illness Index; D013997:Time Factors; D014508:Urea / Q000378:metabolism*
chemical_list: D015415:Biomarkers; D002791:Cholesterol, Dietary; D012333:RNA, Messenger; D014508:Urea; D009954:Ornithine Carbamoyltransferase; D002222:Carbamoyl-Phosphate Synthase (Ammonia)
keywords: hepatic amino nitrogen conversion; metabolism; nonalcoholic fatty liver disease; rats; urea synthesis