TGR5 in the Cholangiociliopathies

A plasma membrane-bound G protein-coupled receptor, TGR5, that transmits bile acid signaling into a cellular response primarily via the cAMP pathway is expressed in human and rodent cholangiocytes and is localized to multiple, diverse subcellular compartments, including primary cilia. Ciliary-associated TGR5 plays an important role in cholangiocyte physiology and may contribute to a group of liver diseases referred to as the 'cholangiociliopathies', which include polycystic liver disease (PLD) and, possibly, cholangiocarcinoma and primary sclerosing cholangitis. Based on our observations that (1) ciliated and nonciliated cholangiocytes respond to TGR5 activation differently (i.e. the level of cAMP increases in nonciliated cholangiocytes but decreases in ciliated cells) and (2) hepatic cysts are derived from cholangiocytes that are characterized by both malformed cilia and increased cAMP levels, we hypothesized that TGR5-mediated cAMP signaling in cystic cholangiocytes contributes to hepatic cystogenesis. Indeed, our studies show that TGR5 is overexpressed and mislocalized in cystic cholangiocytes, and when activated by ligands, results in increased intracellular cAMP levels, cholangiocyte hyperproliferation and cyst growth. Our studies also show that genetic elimination of TGR5 in an animal model of PLD inhibits hepatic cystogenesis. Collectively, these data suggest the involvement of TGR5 in PLD and that TGR5 targeting in cystic cholangiocytes may have therapeutic potential.