PMID- 38286357
OWN - NLM
STAT- MEDLINE
DCOM- 20240219
LR  - 20240219
IS  - 1879-0712 (Electronic)
IS  - 0014-2999 (Linking)
VI  - 966
DP  - 2024 Mar 5
TI  - Farnesoid X receptor agonist tropifexor detoxifies ammonia by regulating the 
      glutamine metabolism and urea cycles in cholestatic livers.
PG  - 176334
LID - S0014-2999(24)00022-0 [pii]
LID - 10.1016/j.ejphar.2024.176334 [doi]
AB  - Hyperammonemia refers to elevated levels of ammonia in the blood, which is an 
      important pathological feature of liver cirrhosis and hepatic failure. 
      Preclinical studies suggest tropifexor (TXR), a novel non-bile acid agonist of 
      Farnesoid X Receptor (FXR), has shown promising effects on reducing hepatic 
      steatosis, inflammation, and fibrosis. This study evaluates the impact of TXR on 
      hyperammonemia in a piglet model of cholestasis. We here observed blood ammonia 
      significantly elevated in patients with biliary atresia (BA) and was positively 
      correlated with liver injury. Targeted metabolomics and immunblotting showed 
      glutamine metabolism and urea cycles were impaired in BA patients. Next, we 
      observed that TXR potently suppresses bile duct ligation (BDL)-induced injuries 
      in liver and brain with improving the glutamine metabolism and urea cycles. 
      Within the liver, TXR enhances glutamine metabolism and urea cycles by 
      up-regulation of key regulatory enzymes, including glutamine synthetase (GS), 
      carbamoyl-phosphate synthetase 1 (CPS1), argininosuccinate synthetase (ASS1), 
      argininosuccinate lyase (ASL), and arginase 1 (ARG1). In primary mice 
      hepatocytes, TXR detoxified ammonia via increasing ureagenesis. Mechanically, TXR 
      activating FXR to increase express enzymes that regulating ureagenesis and 
      glutamine synthesis through a transcriptional approach. Together, these results 
      suggest that TXR may have therapeutic implications for hyperammonemic conditions 
      in cholestatic livers.
CI  - Copyright (c) 2024 Elsevier B.V. All rights reserved.
FAU - Xiao, Yongtao
AU  - Xiao Y
AD  - Department of Pediatric Surgery, Xin Hua Hospital, School of Medicine, Shanghai 
      Jiao Tong University, Shanghai, China; Division of Pediatric Gastroenterology and 
      Nutrition, Xinhua Hospital, School of Medicine, Shanghai Jiao Tong University, 
      Shanghai, China; Shanghai Institute of Pediatric Research, Shanghai, China; 
      Shanghai Key Laboratory of Pediatric Gastroenterology and Nutrition, Shanghai, 
      China. Electronic address: xiaoyongtao@xinhuamed.com.cn.
FAU - Wang, Weipeng
AU  - Wang W
AD  - Department of Pediatric Surgery, Xin Hua Hospital, School of Medicine, Shanghai 
      Jiao Tong University, Shanghai, China; Shanghai Key Laboratory of Pediatric 
      Gastroenterology and Nutrition, Shanghai, China.
FAU - Peng, Shicheng
AU  - Peng S
AD  - Shanghai Institute of Pediatric Research, Shanghai, China; Shanghai Key 
      Laboratory of Pediatric Gastroenterology and Nutrition, Shanghai, China.
FAU - Lu, Ying
AU  - Lu Y
AD  - Shanghai Institute of Pediatric Research, Shanghai, China; Shanghai Key 
      Laboratory of Pediatric Gastroenterology and Nutrition, Shanghai, China.
FAU - Du, Jun
AU  - Du J
AD  - Shanghai Institute of Pediatric Research, Shanghai, China; Shanghai Key 
      Laboratory of Pediatric Gastroenterology and Nutrition, Shanghai, China.
FAU - Cai, Wei
AU  - Cai W
AD  - Department of Pediatric Surgery, Xin Hua Hospital, School of Medicine, Shanghai 
      Jiao Tong University, Shanghai, China; Division of Pediatric Gastroenterology and 
      Nutrition, Xinhua Hospital, School of Medicine, Shanghai Jiao Tong University, 
      Shanghai, China; Shanghai Institute of Pediatric Research, Shanghai, China; 
      Shanghai Key Laboratory of Pediatric Gastroenterology and Nutrition, Shanghai, 
      China. Electronic address: caiw204@sjtu.edu.cn.
LA  - eng
PT  - Journal Article
DEP - 20240128
PL  - Netherlands
TA  - Eur J Pharmacol
JT  - European journal of pharmacology
JID - 1254354
RN  - 0RH81L854J (Glutamine)
RN  - 7664-41-7 (Ammonia)
RN  - NMZ08KM76Z (tropifexor)
RN  - 8W8T17847W (Urea)
RN  - 0 (Isoxazoles)
RN  - 0 (Benzothiazoles)
SB  - IM
MH  - Humans
MH  - Swine
MH  - Mice
MH  - Animals
MH  - Glutamine/metabolism
MH  - Ammonia/metabolism
MH  - *Hyperammonemia/drug therapy/metabolism
MH  - Liver/metabolism
MH  - *Cholestasis/complications/drug therapy/metabolism
MH  - Urea/pharmacology
MH  - *Isoxazoles
MH  - *Benzothiazoles
OTO - NOTNLM
OT  - Ammonia
OT  - Cholestasis
OT  - FXR
OT  - Glutamine metabolism
OT  - Urea cycles
COIS- Declaration of competing interest The authors have no conflicts of interest to 
      disclose.
EDAT- 2024/01/30 00:42
MHDA- 2024/02/19 06:44
CRDT- 2024/01/29 19:16
PHST- 2023/10/10 00:00 [received]
PHST- 2023/12/14 00:00 [revised]
PHST- 2024/01/16 00:00 [accepted]
PHST- 2024/02/19 06:44 [medline]
PHST- 2024/01/30 00:42 [pubmed]
PHST- 2024/01/29 19:16 [entrez]
AID - S0014-2999(24)00022-0 [pii]
AID - 10.1016/j.ejphar.2024.176334 [doi]
PST - ppublish
SO  - Eur J Pharmacol. 2024 Mar 5;966:176334. doi: 10.1016/j.ejphar.2024.176334. Epub 
      2024 Jan 28.