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Suppressed hepatic bile acid signalling despite elevated production of primary and secondary bile acids in NAFLD.

Gut. 2018 Oct;67(10):1881-1891. Epub 2017 Aug 03
Na Jiao 1 , Susan S Baker 2 , Adrian Chapa-Rodriguez 3 , Wensheng Liu 3 , Colleen A Nugent 3 , Maria Tsompana 4 , Lucy Mastrandrea 5 , Michael J Buck 4 , Robert D Baker 3 , Robert J Genco 6 , Ruixin Zhu 1 , Lixin Zhu 2
Na Jiao 1 , Susan S Baker 2 , Adrian Chapa-Rodriguez 3 , Wensheng Liu 3 , Colleen A Nugent 3 , Maria Tsompana 4 , Lucy Mastrandrea 5 , Michael J Buck 4 , Robert D Baker 3 , Robert J Genco 6 , Ruixin Zhu 1 , Lixin Zhu 2
+ et al

[No authors listed]

Author information
  • 1 Department of Bioinformatics, School of Life Sciences and Technology, Tongji University, Shanghai, China.
  • 2 Genome, Environment and Microbiome Community of Excellence, The State University of New York at Buffalo, Buffalo, New York, USA.
  • 3 Department of Pediatrics, Digestive Diseases and Nutrition Center, The State University of New York at Buffalo, Buffalo, New York, USA.
  • 4 Department of Biochemistry and Center of Excellence in Bioinformatics and Life Sciences, The State University of New York at Buffalo, Buffalo, New York, USA.
  • 5 Division of Endocrinology, Department of Pediatrics, The State University of New York at Buffalo, Buffalo, New York, USA.
  • 6 Departments of Oral Biology, Microbiology and Immunology, The State University of New York at Buffalo, Buffalo, New York, USA.

摘要


OBJECTIVE:Bile acids are regulators of lipid and glucose metabolism, and modulate inflammation in the liver and other tissues. Primary bile acids such as cholic acid and chenodeoxycholic acid (CDCA) are produced in the liver, and converted into secondary bile acids such as deoxycholic acid (DCA) and lithocholic acid by gut microbiota. Here we investigated the possible roles of bile acids in non-alcoholic fatty liver disease (NAFLD) pathogenesis and the impact of the gut microbiome on bile acid signalling in NAFLD. DESIGN:Serum bile acid levels and fibroblast growth factor 19 (FGF19), liver gene expression profiles and gut microbiome compositions were determined in patients with NAFLD, high-fat diet-fed rats and their controls. RESULTS:Serum concentrations of primary and secondary bile acids were increased in patients with NAFLD. In per cent, the farnesoid X receptor (FXR) antagonistic DCA was increased, while the agonistic CDCA was decreased in NAFLD. Increased mRNA expression for cytochrome P450 7A1, Na+-taurocholate cotransporting polypeptide and paraoxonase 1, no change in mRNA expression for small heterodimer partner and bile salt export pump, and reduced serum FGF19 were evidence of impaired FXR and fibroblast growth factor receptor 4 (FGFR4)-mediated signalling in NAFLD. Taurine and glycine metabolising bacteria were increased in the gut of patients with NAFLD, reflecting increased secondary bile acid production. Similar changes in liver gene expression and the gut microbiome were observed in high-fat diet-fed rats. CONCLUSIONS:The serum bile acid profile, the hepatic gene expression pattern and the gut microbiome composition consistently support an elevated bile acid production in NAFLD. The increased proportion of FXR antagonistic bile acid explains, at least in part, the suppression of hepatic FXR-mediated and FGFR4-mediated signalling. Our study suggests that future NAFLD intervention may target the components of FXR signalling, including the bile acid converting gut microbiome.

KEYWORDS: bile acid, bile acid metabolism, intestinal microbiology, nonalcoholic steatohepatitis