1. Non‐alcoholic fatty liver disease alters expression of genes governing hepatic nitrogen conversion
- Author
-
Malte P. Suppli, Peter Lykke Eriksen, Kristoffer T. G. Rigbolt, Sanne Skovgård Veidal, Hendrik Vilstrup, Karen Louise Thomsen, Fillip Krag Knop, Michael Sørensen, and Sara Heebøll
- Subjects
Male ,STIMULATION ,UREA CYCLE ,ammonia ,0302 clinical medicine ,Non-alcoholic Fatty Liver Disease ,Gene expression ,Urea ,CIRRHOSIS ,IN-VIVO ,Chemistry ,INDUCTION ,Fatty liver ,glutamine synthetase ,Middle Aged ,Carbamoyl phosphate synthetase ,medicine.anatomical_structure ,Liver ,030220 oncology & carcinogenesis ,Hepatocyte ,Urea cycle ,Female ,030211 gastroenterology & hepatology ,non-alcoholic steatohepatitis ,Adult ,medicine.medical_specialty ,Carbamoyl-Phosphate Synthase (Ammonia) ,urea ,Gene Expression Regulation, Enzymologic ,03 medical and health sciences ,Downregulation and upregulation ,Ammonia ,Glutamate-Ammonia Ligase ,Internal medicine ,medicine ,Humans ,STEATOSIS ,Obesity ,Gene ,ELIMINATION ,amino acids ,Hepatology ,nutritional and metabolic diseases ,medicine.disease ,COMPONENT ,digestive system diseases ,Endocrinology ,glucagon ,Case-Control Studies ,Hepatocytes ,AMINO-ACID-TRANSPORT ,Steatohepatitis ,Transcriptome ,RESISTANCE - Abstract
Background & Aims: 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. Methods: 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. Results: 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 1.5-fold (P ≤.03), inversely related to CPS1 expression (P =.004). Conclusions: 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.
- Published
- 2019