RGD Reference Report - TGR5 contributes to hepatic cystogenesis in rodents with polycystic liver diseases through cyclic adenosine monophosphate/Gαs signaling. - Rat Genome Database

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TGR5 contributes to hepatic cystogenesis in rodents with polycystic liver diseases through cyclic adenosine monophosphate/Gαs signaling.

Authors: Masyuk, Tatyana V  Masyuk, Anatoliy I  Lorenzo Pisarello, Maria  Howard, Brynn N  Huang, Bing Q  Lee, Pui-Yuen  Fung, Xavier  Sergienko, Eduard  Ardecky, Robert J  Chung, Thomas D Y  Pinkerton, Anthony B  LaRusso, Nicholas F 
Citation: Masyuk TV, etal., Hepatology. 2017 Oct;66(4):1197-1218. doi: 10.1002/hep.29284. Epub 2017 Aug 26.
RGD ID: 14700993
Pubmed: PMID:28543567   (View Abstract at PubMed)
PMCID: PMC5605412   (View Article at PubMed Central)
DOI: DOI:10.1002/hep.29284   (Journal Full-text)

Hepatic cystogenesis in polycystic liver disease is associated with increased levels of cyclic adenosine monophosphate (cAMP) in cholangiocytes lining liver cysts. Takeda G protein receptor 5 (TGR5), a G protein-coupled bile acid receptor, is linked to cAMP and expressed in cholangiocytes. Therefore, we hypothesized that TGR5 might contribute to disease progression. We examined expression of TGR5 and Gα proteins in cultured cholangiocytes and in livers of animal models and humans with polycystic liver disease. In vitro, we assessed cholangiocyte proliferation, cAMP levels, and cyst growth in response to (1) TGR5 agonists (taurolithocholic acid, oleanolic acid [OA], and two synthetic compounds), (2) a novel TGR5 antagonist (m-tolyl 5-chloro-2-[ethylsulfonyl] pyrimidine-4-carboxylate [SBI-115]), and (3) a combination of SBI-115 and pasireotide, a somatostatin receptor analogue. In vivo, we examined hepatic cystogenesis in OA-treated polycystic kidney rats and after genetic elimination of TGR5 in double mutant TGR5-/- ;Pkhd1del2/del2 mice. Compared to control, expression of TGR5 and Gαs (but not Gαi and Gαq ) proteins was increased 2-fold to 3-fold in cystic cholangiocytes in vitro and in vivo. In vitro, TGR5 stimulation enhanced cAMP production, cell proliferation, and cyst growth by ∼40%; these effects were abolished after TGR5 reduction by short hairpin RNA. OA increased cystogenesis in polycystic kidney rats by 35%; in contrast, hepatic cystic areas were decreased by 45% in TGR5-deficient TGR5-/- ;Pkhd1del2/del2 mice. TGR5 expression and its colocalization with Gαs were increased ∼2-fold upon OA treatment. Levels of cAMP, cell proliferation, and cyst growth in vitro were decreased by ∼30% in cystic cholangiocytes after treatment with SBI-115 alone and by ∼50% when SBI-115 was combined with pasireotide.
CONCLUSION: TGR5 contributes to hepatic cystogenesis by increasing cAMP and enhancing cholangiocyte proliferation; our data suggest that a TGR5 antagonist alone or concurrently with somatostatin receptor agonists represents a potential therapeutic approach in polycystic liver disease. (Hepatology 2017;66:1197-1218).



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Object Symbol
Species
Term
Qualifier
Evidence
With
Notes
Source
Original Reference(s)
GPBAR1Humanautosomal dominant polycystic kidney disease  IEP mRNA and protein:increased expression: cholangiocyteRGD 
Gpbar1Ratautosomal dominant polycystic kidney disease  ISOGPBAR1 (Homo sapiens)mRNA and protein:increased expression: cholangiocyteRGD 
Gpbar1Mouseautosomal dominant polycystic kidney disease  ISOGPBAR1 (Homo sapiens)mRNA and protein:increased expression: cholangiocyteRGD 
GPBAR1Humanautosomal recessive polycystic kidney disease  IEP mRNA and protein:increased expression: cholangiocyteRGD 
Gpbar1Ratautosomal recessive polycystic kidney disease  ISOGPBAR1 (Homo sapiens)mRNA and protein:increased expression: cholangiocyteRGD 
Gpbar1Mouseautosomal recessive polycystic kidney disease  ISOGPBAR1 (Homo sapiens)mRNA and protein:increased expression: cholangiocyteRGD 
GNASHumanpolycystic kidney disease  ISOGnas (Rattus norvegicus)protein:increased expression:cholangiocyteRGD 
GPBAR1Humanpolycystic kidney disease  ISOGpbar1 (Rattus norvegicus)mRNA and protein:increased expression: cholangiocyteRGD 
GnasRatpolycystic kidney disease  IEP protein:increased expression:cholangiocyteRGD 
GnasMousepolycystic kidney disease  ISOGnas (Rattus norvegicus)protein:increased expression:cholangiocyteRGD 
Gpbar1Ratpolycystic kidney disease  IEP mRNA and protein:increased expression: cholangiocyteRGD 
Gpbar1Mousepolycystic kidney disease  ISOGpbar1 (Rattus norvegicus)mRNA and protein:increased expression: cholangiocyteRGD 
GPBAR1Humanpolycystic liver disease treatmentISOGpbar1 (Mus musculus) RGD 
GPBAR1Humanpolycystic liver disease  ISOGpbar1 (Mus musculus)protein:increased expression: cholangiocyteRGD 
Gpbar1Ratpolycystic liver disease treatmentISOGpbar1 (Mus musculus) RGD 
Gpbar1Ratpolycystic liver disease  ISOGpbar1 (Mus musculus)protein:increased expression: cholangiocyteRGD 
Gpbar1Mousepolycystic liver disease treatmentIMP  RGD 
Gpbar1Mousepolycystic liver disease  IEP protein:increased expression: cholangiocyteRGD 
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Biological Process

  
Object Symbol
Species
Term
Qualifier
Evidence
With
Notes
Source
Original Reference(s)
Gpbar1Ratpositive regulation of cholangiocyte proliferation  IMP  RGD 
Gpbar1Ratpositive regulation of ERK1 and ERK2 cascade  IMP  RGD 


Genes (Rattus norvegicus)
Gnas  (GNAS complex locus) Gpbar1  (G protein-coupled bile acid receptor 1)

Genes (Mus musculus)
Gnas  (GNAS complex locus) Gpbar1  (G protein-coupled bile acid receptor 1)

Genes (Homo sapiens)
GNAS  (GNAS complex locus) GPBAR1  (G protein-coupled bile acid receptor 1)