RGD Reference Report - Suppressed hepatic bile acid signalling despite elevated production of primary and secondary bile acids in NAFLD. - Rat Genome Database

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

Authors: Jiao, Na  Baker, Susan S  Chapa-Rodriguez, Adrian  Liu, Wensheng  Nugent, Colleen A  Tsompana, Maria  Mastrandrea, Lucy  Buck, Michael J  Baker, Robert D  Genco, Robert J  Zhu, Ruixin  Zhu, Lixin 
Citation: Jiao N, etal., Gut. 2018 Oct;67(10):1881-1891. doi: 10.1136/gutjnl-2017-314307. Epub 2017 Aug 3.
RGD ID: 15045601
Pubmed: PMID:28774887   (View Abstract at PubMed)
DOI: DOI:10.1136/gutjnl-2017-314307   (Journal Full-text)


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.



RGD Manual Disease Annotations    Click to see Annotation Detail View

  
Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
CYP27A1Humanmetabolic dysfunction-associated steatohepatitis  IEP mRNA:increased expression:liver (human)RGD 
CYP7A1Humanmetabolic dysfunction-associated steatohepatitis  IEP mRNA:increased expression:liver (human)RGD 
Cyp27a1Ratmetabolic dysfunction-associated steatohepatitis  ISOCYP27A1 (Homo sapiens)mRNA:increased expression:liver (human)RGD 
Cyp27a1Mousemetabolic dysfunction-associated steatohepatitis  ISOCYP27A1 (Homo sapiens)mRNA:increased expression:liver (human)RGD 
Cyp7a1Ratmetabolic dysfunction-associated steatohepatitis  ISOCYP7A1 (Homo sapiens)mRNA:increased expression:liver (human)RGD 
Cyp7a1Mousemetabolic dysfunction-associated steatohepatitis  ISOCYP7A1 (Homo sapiens)mRNA:increased expression:liver (human)RGD 
NR1H4Humanmetabolic dysfunction-associated steatohepatitis  IEP mRNA:increased expression:liver (human)RGD 
Nr1h4Ratmetabolic dysfunction-associated steatohepatitis  ISONR1H4 (Homo sapiens)mRNA:increased expression:liver (human)RGD 
Nr1h4Mousemetabolic dysfunction-associated steatohepatitis  ISONR1H4 (Homo sapiens)mRNA:increased expression:liver (human)RGD 

Molecular Pathway Annotations    Click to see Annotation Detail View

RGD Manual Annotations


  
Objects Annotated

Genes (Rattus norvegicus)
Cyp27a1  (cytochrome P450, family 27, subfamily a, polypeptide 1)
Cyp7a1  (cytochrome P450 family 7 subfamily A member 1)
Nr1h4  (nuclear receptor subfamily 1, group H, member 4)

Genes (Mus musculus)
Cyp27a1  (cytochrome P450, family 27, subfamily a, polypeptide 1)
Cyp7a1  (cytochrome P450, family 7, subfamily a, polypeptide 1)
Nr1h4  (nuclear receptor subfamily 1, group H, member 4)

Genes (Homo sapiens)
CYP27A1  (cytochrome P450 family 27 subfamily A member 1)
CYP7A1  (cytochrome P450 family 7 subfamily A member 1)
NR1H4  (nuclear receptor subfamily 1 group H member 4)


Additional Information