Abstract
The main aim was to evaluate changes in urea cycle enzymes in NAFLD patients and in two preclinical animal models mimicking this entity. Seventeen liver specimens from NAFLD patients were included for immunohistochemistry and gene expression analyses. Three-hundred-and-eighty-two biopsy-proven NAFLD patients were genotyped for rs1047891, a functional variant located in carbamoyl phosphate synthetase-1 (CPS1) gene. Two preclinical models were employed to analyse CPS1 by immunohistochemistry, a choline deficient high-fat diet model (CDA-HFD) and a high fat diet LDLr knockout model (LDLr −/−). A significant downregulation in mRNA was observed in CPS1 and ornithine transcarbamylase (OTC1) in simple steatosis and NASH-fibrosis patients versus controls. Further, age, obesity (BMI > 30 kg/m2), diabetes mellitus and ALT werefound to be risk factors whereas A-allele from CPS1 was a protective factor from liver fibrosis. CPS1 hepatic expression was diminished in parallel with the increase of fibrosis, and its levels reverted up to normality after changing diet in CDA-HFD mice. In conclusion, liver fibrosis and steatosis were associated with a reduction in both gene and protein expression patterns of mitochondrial urea cycle enzymes. A-allele from a variant on CPS1 may protect from fibrosis development. CPS1 expression is restored in a preclinical model when the main trigger of the liver damage disappears.
Highlights
The main aim was to evaluate changes in urea cycle enzymes in Non-alcoholic fatty liver disease (NAFLD) patients and in two preclinical animal models mimicking this entity
Patients were selected as bland steatosis (n = 10), defined as steatosis presence, nor steatohepatitis or fibrosis, and Non-alcoholic steatohepatitis (NASH) with fibrosis (n = 7)
Seven healthy controls were included for gene expression analyses
Summary
The main aim was to evaluate changes in urea cycle enzymes in NAFLD patients and in two preclinical animal models mimicking this entity. Abbreviations NAFLD Non-alcoholic fatty liver disease NASH Non-alcoholic steatohepatitis CPS1 Carbamoyl phosphate synthetase-1 CDA-HFD Choline deficient high-fat diet model LDLr −/− LDLr knockout model OTC1 Ornithine transcarbamylase UCEs Urea cycle enzymes. Non-alcoholic steatohepatitis (NASH) is a condition histologically characterized by inflammation, ballooning degeneration and may be or not accompanied by liver fibrosis, together with the typical fatty hepatocytes, in absence of relevant alcohol consumption. This entity has surfaced as a major health problem worldwide, due to its high global prevalence, reaching 25%, and not negligible hepatocellular carcinoma progression and mortality r ates[2]. It has been linked to several clinical conditions, such as differential serum lipid profiles in certain ethnic g roups[10] and A-allele carriers seem to be more prone to develop hyperammonemia associated to valproic acid intake for the treatment of e pilepsy[11]
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
