Liver injury in non-alcoholic fatty liver disease is associated with urea cycle enzyme dysregulation.

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 were found 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.

• Authors: Rocío Gallego-Durán, Javier Ampuero, Helena Pastor-Ramírez, Leticia Álvarez-Amor, Jose Antonio Del Campo, Douglas Maya-Miles, Rocío Montero-Vallejo, Antonio Cárdenas-García, Mª Jesús Pareja, Sheila Gato-Zambrano, Raquel Millán, María Del Carmen Rico, Amparo Luque-Sierra, Antonio Gil-Gómez, Ángela Rojas, Rocío Muñoz-Hernández, María García-Lozano, Rocío Aller, Raúl J Andrade, Carmelo García-Monzón, Fausto Andreola, Francisco Martín, Rajiv Jalan, Manuel Romero-Gómez
• Journal: Scientific reports (Sci Rep) Vol. 12 Issue 1 Pg. 3418 (03 01 2022) ISSN: 2045-2322 [Electronic] England
• PMID: 35232986 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2022. The Author(s).

Chemical References

• Urea
• Carbamoyl-Phosphate Synthase (Ammonia)

Topics

• Animals
• Carbamoyl-Phosphate Synthase (Ammonia) (genetics, metabolism)
• Diet, High-Fat (adverse effects)
• Disease Models, Animal
• Humans
• Liver (metabolism)
• Liver Cirrhosis (pathology)
• Mice
• Mice, Inbred C57BL
• Non-alcoholic Fatty Liver Disease (metabolism)
• Urea (metabolism)