The most significant article on primary sclerosing cholangitis (PSC) published in August 2010 was this full text article from the Norwegian PSC Research Center, Clinic for Specialized Medicine and Surgery, Oslo University Hospital Rikshospitalet, Oslo, Norway:

Hov JR, Keitel V, Laerdahl JK, Spomer L, Ellinghaus E, ElSharawy A, Melum E, Boberg KM, Manke T, Balschun T, Schramm C, Bergquist A, Weismuller T, Gotthardt D, Rust C, Henckaerts L, Onnie CM, Weersma RK, Sterneck M, Teufel A, Runz H, Stiehl A, Ponsioen CY, Wijmenga C, Vatn MH; IBSEN Study Group, Stokkers PC, Vermeire S, Mathew CG, Lie BA, Beuers U, Manns MP, Schreiber S, Schrumpf E, Haussinger D, Franke A, Karlsen TH. Mutational characterization of the bile acid receptor TGR5 in primary sclerosing cholangitis. PLoS One 5 pii: e12403 (2010)

Some background articles on TGR5, the G protein-coupled bile acid receptor 1 (GPBAR1), and their relevance to PSC are as follows. Previous research from the Norwegian PSC Research Center established TGR5 as a candidate susceptibility gene in human PSC:

Karlsen TH, Franke A, Melum E, Kaser A, Hov JR, Balschun T, Lie BA, Bergquist A, Schramm C, Weismuller TJ, Gotthardt D, Rust C, Philipp EE, Fritz T, Henckaerts L, Weersma RK, Stokkers P, Ponsioen CY, Wijmenga C, Sterneck M, Nothnagel M, Hampe J, Teufel A, Runz H, Rosenstiel P, Stiehl A, Vermeire S, Beuers U, Manns MP, Schrumpf E, Boberg KM, Schreiber S. Genome-wide association analysis in primary sclerosing cholangitis. Gastroenterology 138: 1102-1111 (2010)

TGR5 is strongly expressed in the primary cilium of cholangiocytes, where it may play an important role in coupling biliary bile acid concentration and composition to ductular bile formation:

Keitel V, Ullmer C, Haussinger D. The membrane-bound bile acid receptor TGR5 (Gpbar-1) is localized in the primary cilium of cholangiocytes. Biol. Chem. 391: 785-789 (2010)

TGR5 is a component of the biliary bicarbonate secretion machinery in the liver and gallbladder, and may serve as a regulator of the cystic fibrosis transmembrane conductance regulator (CFTR) involved in bicarbonate secretion into bile:

Beuers U, Hohenester S, de Buy Wenniger LJ, Kremer AE, Jansen PL, Elferink RP. The biliary HCO(3) (-) umbrella: a unifying hypothesis on pathogenetic and therapeutic aspects of fibrosing cholangiopathies. Hepatology Jun 16 [Epub ahead of print] (2010)
Keitel V, Cupisti K, Ullmer C, Knoefel WT, Kubitz R, Haussinger D. The membrane-bound bile acid receptor TGR5 is localized in the epithelium of human gallbladders. Hepatology 50: 861-870 (2009)

Previous studies have shown that there may be impaired function of the cystic fibrosis transmembrane conductance regulator (CFTR) in pediatric PSC patients..."There is a high prevalence of CFTR-mediated ion transport dysfunction in subjects with childhood PSC":

Pall H, Zielenski J, Jonas MM, DaSilva DA, Potvin KM, Yuan XW, Huang Q, Freedman SD. Primary sclerosing cholangitis in childhood is associated with abnormalities in cystic fibrosis-mediated chloride channel function. J. Pediatr. 151: 255-259 (2007)

It is well known that the liver disease associated with cystic fibrosis strongly resembles PSC, and work by Freedman and colleagues have identified an increased prevalence of CFTR mutations and variants in human PSC:

Sheth S, Shea JC, Bishop MD, Chopra S, Regan MM, Malmberg E, Walker C, Ricci R, Tsui LC, Durie PR, Zielenski J, Freedman SD. Increased prevalence of CFTR mutations and variants and decreased chloride secretion in primary sclerosing cholangitis. Hum. Genet. 113: 286-292 (2003)

Because of the involvement of TGR5 in regulating CFTR and bicarbonate secretion into bile, further work on the mutations in TGR5 and CFTR associated with PSC should be helpful in clarifying the pathogenesis of PSC.

www psc-literature.org

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