{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T17:17:33Z","timestamp":1790788653627,"version":"4.1.0"},"reference-count":41,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"4","license":[{"start":{"date-parts":[[2017,8,26]],"date-time":"2017-08-26T00:00:00Z","timestamp":1503705600000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"},{"start":{"date-parts":[[2017,8,26]],"date-time":"2017-08-26T00:00:00Z","timestamp":1503705600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":["lww.com","ovid.com"],"crossmark-restriction":true},"short-container-title":["Hepatology"],"published-print":{"date-parts":[[2017,10]]},"abstract":"<jats:p>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\u2013coupled 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 G\u03b1 proteins in cultured cholangiocytes and in livers of animal models and humans with polycystic liver disease. <jats:italic toggle=\"yes\">In vitro<\/jats:italic>, 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\u2010tolyl 5\u2010chloro\u20102\u2010[ethylsulfonyl] pyrimidine\u20104\u2010carboxylate [SBI\u2010115]), and (3) a combination of SBI\u2010115 and pasireotide, a somatostatin receptor analogue. <jats:italic toggle=\"yes\">In vivo<\/jats:italic>, we examined hepatic cystogenesis in OA\u2010treated polycystic kidney rats and after genetic elimination of TGR5 in double mutant <jats:italic toggle=\"yes\">TGR5\u2212\/\u2212\n                           <\/jats:italic>;<jats:italic toggle=\"yes\">Pkhd1del2\/del2\n                           <\/jats:italic> mice. Compared to control, expression of TGR5 and G\u03b1<jats:sub>s<\/jats:sub> (but not G\u03b1<jats:sub>i<\/jats:sub> and G\u03b1<jats:sub>q<\/jats:sub>) proteins was increased 2\u2010fold to 3\u2010fold in cystic cholangiocytes <jats:italic toggle=\"yes\">in vitro<\/jats:italic> and <jats:italic toggle=\"yes\">in vivo<\/jats:italic>. <jats:italic toggle=\"yes\">In vitro<\/jats:italic>, TGR5 stimulation enhanced cAMP production, cell proliferation, and cyst growth by \u223c40%; 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\u2010deficient <jats:italic toggle=\"yes\">TGR5\u2212\/\u2212;Pkhd1del2\/del2\n                           <\/jats:italic> mice. TGR5 expression and its colocalization with G\u03b1<jats:sub>s<\/jats:sub> were increased \u223c2\u2010fold upon OA treatment. Levels of cAMP, cell proliferation, and cyst growth <jats:italic toggle=\"yes\">in vitro<\/jats:italic> were decreased by \u223c30% in cystic cholangiocytes after treatment with SBI\u2010115 alone and by \u223c50% when SBI\u2010115 was combined with pasireotide. <jats:italic toggle=\"yes\">Conclusion:<\/jats:italic> 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. (H<jats:sc>epatology<\/jats:sc> 2017;66:1197\u20101218).<\/jats:p>","DOI":"10.1002\/hep.29284","type":"journal-article","created":{"date-parts":[[2017,5,25]],"date-time":"2017-05-25T11:57:48Z","timestamp":1495713468000},"page":"1197-1218","update-policy":"https:\/\/doi.org\/10.1097\/lww.0000000000001000","source":"Crossref","is-referenced-by-count":66,"title":["TGR5 contributes to hepatic cystogenesis in rodents with polycystic liver diseases through cyclic adenosine monophosphate\/G\u03b1s signaling"],"prefix":"10.1097","volume":"66","author":[{"given":"Tatyana V.","family":"Masyuk","sequence":"first","affiliation":[{"name":"Division of Gastroenterology and Hepatology,Mayo Clinic,Rochester,MN"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anatoliy I.","family":"Masyuk","sequence":"additional","affiliation":[{"name":"Division of Gastroenterology and Hepatology,Mayo Clinic,Rochester,MN"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria","family":"Lorenzo Pisarello","sequence":"additional","affiliation":[{"name":"Division of Gastroenterology and Hepatology,Mayo Clinic,Rochester,MN"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brynn N.","family":"Howard","sequence":"additional","affiliation":[{"name":"Division of Gastroenterology and Hepatology,Mayo Clinic,Rochester,MN"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bing Q.","family":"Huang","sequence":"additional","affiliation":[{"name":"Division of Gastroenterology and Hepatology,Mayo Clinic,Rochester,MN"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pui\u2010Yuen","family":"Lee","sequence":"additional","affiliation":[{"name":"Division of Gastroenterology and Hepatology,Mayo Clinic,Rochester,MN"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xavier","family":"Fung","sequence":"additional","affiliation":[{"name":"Division of Gastroenterology and Hepatology,Mayo Clinic,Rochester,MN"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eduard","family":"Sergienko","sequence":"additional","affiliation":[{"name":"Conrad Prebys Center for Chemical Genomics at Sanford\u2010Burnham Prebys Medical,Discovery Institute,La Jolla,CA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert J.","family":"Ardecky","sequence":"additional","affiliation":[{"name":"Conrad Prebys Center for Chemical Genomics at Sanford\u2010Burnham Prebys Medical,Discovery Institute,La Jolla,CA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas D.Y.","family":"Chung","sequence":"additional","affiliation":[{"name":"Office of Translation to Practice,Mayo 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