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Non-alcoholic fatty liver disease alters expression of genes governing hepatic nitrogen conversion.

Authors
  • Eriksen, Peter Lykke1
  • Vilstrup, Hendrik1
  • Rigbolt, Kristoffer2
  • Suppli, Malte P3
  • Sørensen, Michael1
  • Heebøll, Sara1
  • Veidal, Sanne S2
  • Knop, Fillip K3, 4, 5, 6
  • Thomsen, Karen Louise1
  • 1 Department of Hepatology and Gastroenterology, Aarhus University Hospital, Aarhus, Denmark. , (Denmark)
  • 2 Gubra, Hørsholm, Denmark. , (Denmark)
  • 3 Center for Clinical Metabolic Research, Gentofte Hospital, University of Copenhagen, Hellerup, Denmark. , (Denmark)
  • 4 Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark. , (Denmark)
  • 5 Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark. , (Denmark)
  • 6 Steno Diabetes Center Copenhagen, Gentofte, Denmark. , (Denmark)
Type
Published Article
Journal
Liver international : official journal of the International Association for the Study of the Liver
Publication Date
Nov 01, 2019
Volume
39
Issue
11
Pages
2094–2101
Identifiers
DOI: 10.1111/liv.14205
PMID: 31386258
Source
Medline
Keywords
Language
English
License
Unknown

Abstract

We recently showed that the functional capacity for ureagenesis is deficient in non-alcoholic fatty liver disease (NAFLD) patients. The aim of this study was to assess expression of urea cycle-related genes to elucidate a possible gene regulatory basis to the functional problem. Liver mRNA expression analyses within the gene pathway governing hepatic nitrogen conversion were performed in 20 non-diabetic, biopsy-proven NAFLD patients (8 simple steatosis; 12 non-alcoholic steatohepatitis [NASH]) and 12 obese and 14 lean healthy individuals. Sixteen NAFLD patients were included for gene expression validation. Relationship between gene expressions and functional capacity for ureagenesis was described. Gene expression of most urea cycle-related enzymes were downregulated in NAFLD vs both control groups; markedly so for the urea cycle flux-generating carbamoyl phosphate synthetase (CPS1) (~3.5-fold, P < .0001). In NASH, CPS1 downregulation paralleled the deficit in ureagenesis (P = .03). Additionally, expression of several genes involved in amino acid uptake and degradation, and the glucagon receptor gene, were downregulated in NAFLD. Conversely, glutamine synthetase (GS) expression increased >1.5-fold (P ≤ .03), inversely related to CPS1 expression (P = .004). NAFLD downregulated the expression of urea cycle-related genes. Downregulation of urea cycle flux-generating CPS1 correlated with the loss of functional capacity for ureagenesis in NASH. On gene level, these changes coincided with an increase in the major ammonia scavenging enzyme GS. The effects seemed related to a fatty liver as such rather than NASH or obesity. The findings support gene regulatory mechanisms involved in the deficient ureagenesis of NAFLD, but it remains unexplained how hepatocyte fat accumulation exerts these effects. © 2019 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

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