Non-alcoholic fatty liver disease alters expression of genes governing hepatic nitrogen conversion
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Non-alcoholic fatty liver disease alters expression of genes governing hepatic nitrogen conversion. / Eriksen, Peter Lykke; Vilstrup, Hendrik; Rigbolt, Kristoffer; Suppli, Malte P.; Sørensen, Michael; Heebøll, Sara; Veidal, Sanne S.; Knop, Fillip K.; Thomsen, Karen Louise.
In: Liver International, Vol. 39, No. 11, 2019, p. 2094-2101.Research output: Contribution to journal › Journal article › Research › peer-review
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TY - JOUR
T1 - Non-alcoholic fatty liver disease alters expression of genes governing hepatic nitrogen conversion
AU - Eriksen, Peter Lykke
AU - Vilstrup, Hendrik
AU - Rigbolt, Kristoffer
AU - Suppli, Malte P.
AU - Sørensen, Michael
AU - Heebøll, Sara
AU - Veidal, Sanne S.
AU - Knop, Fillip K.
AU - Thomsen, Karen Louise
PY - 2019
Y1 - 2019
N2 - 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 <.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). 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.
AB - 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 <.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). 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.
KW - amino acids
KW - ammonia
KW - glucagon
KW - glutamine synthetase
KW - non-alcoholic steatohepatitis
KW - urea
U2 - 10.1111/liv.14205
DO - 10.1111/liv.14205
M3 - Journal article
C2 - 31386258
AN - SCOPUS:85071855933
VL - 39
SP - 2094
EP - 2101
JO - Liver International
JF - Liver International
SN - 1478-3223
IS - 11
ER -
ID: 231904541