Experimental nonalcoholic steatohepatitis compromises ureagenesis, an essential hepatic metabolic function

Thomsen, Karen Louise, Grønbæk, Henning, Glavind, Emilie, Hebbard, Lionel, Jessen, Niels, Clouston, Andrew, George, Jacob, and Vilstrup, Hendrik (2014) Experimental nonalcoholic steatohepatitis compromises ureagenesis, an essential hepatic metabolic function. Gastrointestinal and liver physiology, 307 (3). G295-G301.

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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.

Item ID: 40185
Item Type: Article (Research - C1)
ISSN: 1522-1547
Keywords: hepatic amino nitrogen conversion; metabolism; nonalcoholic fatti liver disease; rats; urea synthesis
Funders: Fonden til Lægevidenskabens Fremme, Danske Lægers Forsikring under Codan, NOVO Nordisk Foundation, Aarhus University, Robert W. Storr Bequest to the Sydney Medical Foundation of the University of Sydney, National Health and Medical Research Council (NHMRC)
Projects and Grants: NHMRC Grant No. 1053206, NHMRC Grant No. 632630, NHMRC Grant No. 1049857
Date Deposited: 26 Aug 2015 03:18
FoR Codes: 11 MEDICAL AND HEALTH SCIENCES > 1101 Medical Biochemistry and Metabolomics > 110102 Medical Biochemistry: Carbohydrates @ 100%
SEO Codes: 92 HEALTH > 9201 Clinical Health (Organs, Diseases and Abnormal Conditions) > 920105 Digestive System Disorders @ 100%
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