De Chiara, F;
Heebøll, S;
Marrone, G;
Hamilton-Dutoit, S;
Ferrandez, A;
Andreola, F;
Rombouts, K;
... Thomsen, KL; + view all
(2018)
Urea cycle dysregulation in non-alcoholic fatty liver disease.
Journal of Hepatology
, 69
(4)
pp. 905-915.
10.1016/j.jhep.2018.06.023.
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Abstract
Background: In non-alcoholic steatohepatitis (NASH), function of urea cycle enzymes (UCEs) may be affected and result in hyperammonemia with risk of disease progression. We aimed to determine whether expression and function of UCEs are altered in a NASH animal model and in non-alcoholic fatty liver disease (NAFLD) patients and whether this is reversible. / Methods: Rats were fed a high-fat, high-cholesterol diet for 10 months to induce NASH and then changed to normal chow to recover. In humans, we obtained liver biopsies from 20 patients with steatosis and 15 NASH patients. Primary rat hepatocytes were isolated and cultured with free fatty acids. We measured the gene and protein expression, the activity of ornithine transcarbamylase (OTC) and ammonia concentrations. Moreover, we assessed the promoter methylation status of OTC and carbamoyl phosphate synthetase (CPS1) in rats, humans and in steatotic hepatocytes. / Results: In NASH animals, gene and protein expression of OTC and CPS1 and activity of OTC were reversibly reduced and hypermethylation of OTC promotor genes was observed. Also in NAFLD patients, OTC enzyme concentration and activity were reduced and ammonia concentrations were increased and more so in NASH. Furthermore, OTC and CPS1 promoter regions were hypermethylated. In primary hepatocytes induction of steatosis was associated with OTC promoter hypermethylation, reduction in the gene expression of OTC and CPS1 and an increase in ammonia concentration in the supernatant. / Conclusion: NASH is associated with a reduction in gene and protein expression, and activity of UCEs resulting in hyperammonemia, possibly through hypermethylation of UCE genes and impairment of urea synthesis. Our investigations describe for the first time a link between NASH, function of UCEs and hyperammonemia providing a novel therapeutic target. / Lay summary: In patients with fatty liver disease, the enzymes that convert nitrogen waste into urea may be affected leading to the accumulation of the toxic substance, ammonia. This accumulation of ammonia can lead to development of scar tissue and risk of progression of disease. In this study, we show that fat accumulation in the liver produces a reversible reduction in the function of these enzymes that are involved in detoxification of ammonia. These data provide potential new targets for therapy of fatty liver disease.
| Type: | Article |
|---|---|
| Title: | Urea cycle dysregulation in non-alcoholic fatty liver disease |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1016/j.jhep.2018.06.023 |
| Publisher version: | http://dx.doi.org/10.1016/j.jhep.2018.06.023 |
| Language: | English |
| Additional information: | This version is the author accepted manuscript. For information on re-use, please refer to the publisher’s terms and conditions. |
| Keywords: | Ammonia, Epigenetic modifications, Non-alcoholic fatty liver disease, Non-alcoholic steatohepatitis, Urea synthesis |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine > Inst for Liver and Digestive Hlth |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10052075 |
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