TGR5 in the Cholangiociliopathies
Open accessAbstract
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.
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Cholangiocyte cilia are enriched for P2RY12 and GPBAR1/TGR5, as well as adenylyl cyclase, PKA, EPAC2, and AKAP150.
“cholangiocyte cilia are enriched for two different GPCRs — purinergic receptor P2Y12 (P2RY12) 155 and G-protein coupled bile acid receptor 1 (GPBAR1, also known as TGR5) 157, 158, as well as the cAMP signalling proteins adenylyl cyclase, PKA, exchange protein directly activated by cAMP isoform 2 (EPAC2), and A-kinase anchoring protein (AKAP150) 155”
From Cellular signalling by primary cilia in development, organ function and disease (2019) · cites this paper as [158]
The presence or absence of cilia might affect GPBAR1 signalling.
“The presence or absence of cilia might also affect GPBAR1 signalling 158.”
From Cellular signalling by primary cilia in development, organ function and disease (2019) · cites this paper as [158]
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- Authors
- Masyuk, T. V., Masyuk, A. I., & LaRusso, N. F.
- Affiliations
- Mayo Clinic (US)
- Venue
- Digestive Diseases
- Publisher
- S. Karger AG
- Published
- 2015
- Volume
- 33
- Issue
- 3
- Pages
- 420-425
- ISSN
- 0257-2753 (ISSN-L)
- 1421-9875
- PMC
- PMC4523139
- OpenAlex
- W1574471242
- Cited by
- 29
- References
- 37
- Citations by year
- 2025: 2 · 2023: 3 · 2022: 3 · 2021: 2 · 2020: 3 · 2019: 2 · 2018: 5 · 2017: 7 · 2016: 2
- FWCI
- 3.19
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Digestive Diseases (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institute of Diabetes and Digestive and Kidney Diseases (R01DK024031, P30DK084567, R01DK057993)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic and Kidney Cyst Diseases
- Health Sciences › Medicine › Oncology › Drug Transport and Resistance Mechanisms
- Health Sciences › Medicine › Surgery › Pediatric Hepatobiliary Diseases and Treatments
- Keywords
- TGR5, polycystic liver disease, bile acid signaling, cAMP signaling, cholangiocytes, primary cilia, cholangiocarcinoma, primary sclerosing cholangitis, G protein-coupled receptors
- MeSH terms
- Cyclic AMP, Bile Duct Neoplasms, Bile Ducts, Cilia, Cysts, Epithelial Cells, Humans, Liver Diseases, Cholangitis, Sclerosing, Signal Transduction, Cholangiocarcinoma, Receptors, G-Protein-Coupled
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