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Hepatic cystogenesis in Polycystic Liver Disease (PLD) is associated with increased levels of cAMP in cholangiocytes lining liver cysts. 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 PLD. In vitro, we assessed cholangiocyte proliferation, cAMP levels, and cyst growth in response to: (i) TGR5 agonists [taurolithocholic acid (TLCA), oleanolic acid (OA) and two synthetic compounds]; (ii) a novel TGR5 antagonist (SBI-115); and (iii) a combination of SBI-115 and pasireotide, a somatostatin receptor (SSTR) analog. In vivo, we examined hepatic cystogenesis in OA-treated PCK 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 2–3-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 shRNA. OA increased cystogenesis in PCK rats by 35%; in contrast, hepatic cystic areas were decreased by 45% in TGR5-deficient TGR5−/−;Pkhd1del2/del2 mice. TGR5 expression and its co-localization 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 SSTR agonists represents novel therapeutic approaches in PLD.

It has been reported that the incidence of lung cancer is higher in patients with pulmonary tuberculosis (TB). However, there is little information on the survival and clinical characteristics of these patients. We retrospectively reviewed the medical records of patients with coexisting pulmonary TB and lung cancer covering a period from 1988 to 1994. There were 31 such patients among a total of 3928 lung cancers diagnosed. Lung cancer patients had an increased risk of active pulmonary TB in comparison with the general population in Taiwan. Diabetes mellitus (DM) was found in 37.5% of patients who were diagnosed as having active pulmonary TB within 2 years before, or concurrent with, the diagnosis of lung cancer. However, none of the patients who had developed lung cancer before TB had a history of DM. Epidermoid carcinoma accounted for 64.5% of these cases. The patients who had developed active pulmonary TB before, or concurrently with, the diagnosis of lung cancer survived shorter than those who did not have pulmonary TB at diagnosis of lung cancer (P=0.007). Survival from diagnosis of pulmonary TB was longer in patients who developed the disease earlier than lung cancer (P=0.046). Survival from the time of diagnosis of lung cancer was significantly longer in patients who developed cancer earlier than active pulmonary TB (P=0.0048), those without DM (P=0.0132), those with an early tumor stage (P=0.002), and those given specific cancer treatment (P=0.0001). It is concluded that survival is shorter in lung cancer patients who present initially with active TB than in those who do not have TB.

PubMed search (April 2017) was done with the following terms: "microRNA", "miRNA", "miR", "extracellular vesicles", "EV", "exosomes", "primary biliary cholangitis", "primary biliary cholangitis", "PBC", "primary sclerosing cholangitis", "PSC", "cholangiocarcinoma", "CCA", "biliary atresia", "BA", "polycystic liver diseases", "PLD", "cholangiopathies", "cholestatic liver disease". Most significant articles in full-text English were selected. The reference lists of selected papers were also considered.