OCA has recently been approved for the treatment

OCA has recently been approved for the treatment of patients with PBC and is under study for diseases such as NASH, PSC and biliary atresia [30], [49]. Up to now, the beneficial effects of OCA have been related to its anti-cholestatic, anti-inflammatory and anti-fibrotic properties. We have here reported the therapeutic value of OCA in CCA, affecting tumor growth in immunodeficient mice as well as CCA cell proliferation, migration and mitochondrial energy metabolism in vitro. These data are consistent with previous reports showing the inhibitory effect of the synthetic non-steroidal isoxazole-based FXR agonists GW4064 on the subcutaneous growth of CCA AZ20 in nude mice [50]. Since FXR activation has been described to promote chemosensitization [51], the effect of OCA together with chemotherapy should also be evaluated in the near future. Based on our data, inhibition of TGR5 activity might also have therapeutic value for CCA. Previous studies have reported that TGR5 activation stimulates adenylate-cyclase and increases intracellular cAMP production, which subsequently activates protein kinase A (PKA) and cholangiocyte proliferation via EGFR/ERK [52]. In addition, TGR5 activation was reported to specifically stimulate the proliferation of non-ciliated cholangiocytes [53] as well as the survival to apoptosis in normal cholangiocytes [52]. CCA human cells are characterized by a shorter or even absent primary cilia compared to NHCs, thus, the pro-tumoral effects of TGR5 activation in CCA cells could be related to ciliary abnormalities in CCA cells. Our data indicating the pro-metastatic features of TGR5 activation in CCA cells are consistent with the fact that conjugated BAs such as taurocholate are known to increase CCA invasiveness [7]. In line with this, INT-777 was reported to stimulate gastric cancer cell migration [27]. TGR5 has also been suggested to play a role in inflammation. Activation of TGR5 in hepatic Kupffer cells reduces LPS-induced pro-inflammatory cytokine production [54]. Based on these data and the fact that TGR5 activation in mice promotes protective mechanisms in biliary epithelial cells (as it contributes to the maintenance of the so-called ‘bicarbonate umbrella’) and reduces hepatic and systemic inflammation [55], TGR5 agonists were suggested for the treatment of PSC patients [55]. However, PSC is a well-known risk factor of CCA and 10–15% of PSC patients develop CCA [56]. As per our data TGR5 activation shows pro-tumorigenic properties in CCA progression and dissemination, the potential treatment of PSC patients with TGR5 agonists needs further investigation.
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Introduction Alcoholic liver disease (ALD) is caused by chronic and overt alcohol consumption, and is one of the major causes of liver morbidity and mortality worldwide. The mechanisms underlying ALD pathogenesis are complex and remain elusive. The currently accepted concept is that alcohol consumption causes gut leakage-induced inflammation, alters hepatic metabolism, increases oxidative stress and alters lipid metabolism, which collectively leads to hepatotoxicity [1], [2], [3], [4]. In addition to the amount of alcohol intake, environmental and genetic factors play crucial roles in ALD development. These factors include gender, ethnicity, nutritional factors and hepatic co-morbid conditions [3], [4], [5]. ALD is recognized as a progressive disease which comprises a wide spectrum of liver pathologies. The morphological changes in ALD range from hepatic steatosis, inflammation, and fibrosis culminating to alcoholic cirrhosis and potentially hepatocellular carcinoma [4], [5], [6]. FXR is a ligand-activated transcription factor belonging to the nuclear receptor superfamily, and is essential for regulating lipid and bile acid (BA) homeostasis [7], [8], [9]. Moreover, FXR also protects the liver against inflammation [10], [11], [12] and chemical-induced liver injury [13], [14]. BAs are endogenous ligands of FXR, and critical for solublization and absorption of dietary lipids and fat-soluble vitamins in the intestine [15]. In addition, BAs function as important signaling molecules and activate various cell signaling pathways [15]. Juxtaposed to their beneficial roles, BAs can also be toxic with high concentrations of causing cell injury, apoptosis [15], [16], and promotion of tumorigenesis in the liver and intestine [15], [17]. Therefore, BA levels in the body need to be tightly controlled.