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Farnesoid X Receptor Activation Promotes Hepatic Amino Acid Catabolism and Ammonium Clearance in Mice
- Source :
- Gastroenterology, 152(6), 1462. W.B. Saunders Ltd
- Publication Year :
- 2017
-
Abstract
- Background & Aims The nuclear receptor subfamily 1 group H member 4 (NR1H4 or farnesoid X receptor [FXR]) regulates bile acid synthesis, transport, and catabolism. FXR also regulates postprandial lipid and glucose metabolism. We performed quantitative proteomic analyses of liver tissues from mice to evaluate these functions and investigate whether FXR regulates amino acid metabolism. Methods To study the role of FXR in mouse liver, we used mice with a disruption of Nr1h4 (FXR-knockout mice) and compared them with floxed control mice. Mice were gavaged with the FXR agonist obeticholic acid or vehicle for 11 days. Proteome analyses, as well as targeted metabolomics and chromatin immunoprecipitation, were performed on the livers of these mice. Primary rat hepatocytes were used to validate the role of FXR in amino acid catabolism by gene expression and metabolomics studies. Finally, control mice and mice with liver-specific disruption of Nr1h4 (liver FXR-knockout mice) were re-fed with a high-protein diet after 6 hours fasting and gavaged a 15 NH 4 Cl tracer. Gene expression and the metabolome were studied in the livers and plasma from these mice. Results In livers of control mice and primary rat hepatocytes, activation of FXR with obeticholic acid increased expression of proteins that regulate amino acid degradation, ureagenesis, and glutamine synthesis. We found FXR to bind to regulatory sites of genes encoding these proteins in control livers. Liver tissues from FXR-knockout mice had reduced expression of urea cycle proteins, and accumulated precursors of ureagenesis, compared with control mice. In liver FXR-knockout mice on a high-protein diet, the plasma concentration of newly formed urea was significantly decreased compared with controls. In addition, liver FXR-knockout mice had reduced hepatic expression of enzymes that regulate ammonium detoxification compared with controls. In contrast, obeticholic acid increased expression of genes encoding enzymes involved in ureagenesis compared with vehicle in C57Bl/6 mice. Conclusions In livers of mice, FXR regulates amino acid catabolism and detoxification of ammonium via ureagenesis and glutamine synthesis. Failure of the urea cycle and hyperammonemia are common in patients with acute and chronic liver diseases; compounds that activate FXR might promote ammonium clearance in these patients.
- Subjects :
- Male
0301 basic medicine
Glutamine Synthetase
Proteome
Cytoplasmic and Nuclear
Glutamine
Wistar
Gene Expression
Receptors, Cytoplasmic and Nuclear
Inbred C57BL
Mice
chemistry.chemical_compound
INT-747
Chenodeoxycholic acid
Receptors
Urea
Mice, Knockout
Bile acid
Gastroenterology
Obeticholic acid
Liver Proteome
Liver
Biochemistry
Urea cycle
Metabolome
Dietary Proteins
medicine.medical_specialty
medicine.drug_class
Knockout
Cps1
Biology
Chenodeoxycholic Acid
Bile Acids and Salts
03 medical and health sciences
Ammonia
Internal medicine
medicine
Journal Article
Animals
Rats, Wistar
Liver X receptor
Hepatology
Catabolism
Rats
Mice, Inbred C57BL
030104 developmental biology
Endocrinology
chemistry
Hepatocytes
Farnesoid X receptor
Subjects
Details
- Language :
- English
- ISSN :
- 00165085
- Database :
- OpenAIRE
- Journal :
- Gastroenterology, 152(6), 1462. W.B. Saunders Ltd
- Accession number :
- edsair.doi.dedup.....4a85c10a058347b17e81f119b1883b74