Dataset on transcriptomic profiling of cholestatic liver injury in an in vitro and in vivo animal model

The transcriptomic dataset (whole genome microarray Affymetrix Human U133 plus 2.0 and Affymetrix Mouse Genome 430 2.0) presented in this paper describes the differential gene expression profile of a human in vitro model of drug-induced cholestasis and a well-known mouse in vivo model of cholestasis. The in vitro model consists of human hepatoma HepaRG cells in monolayer configuration exposed to 3 different cholestatic drugs with or without bile acids. For in vivo modelling of cholestasis, mice were subjected to bile duct ligation surgery. Consecutive normalization, summarization and background adjustments have been made by means of Robust Multichip Average Express software. (C) 2020 The Author(s). Published by Elsevier Inc

The angiopoietin/tie2 pathway in hepatocellular carcinoma

Due to the usually late diagnosis and lack of effective therapies, hepatocellular carcinoma (HCC), which poses a growing global health problem, is characterized by a poor prognosis. Angiogenesis plays an important role in HCC progression, and vascular endothelial growth factor (VEGF) and angiopoietins (Angs) are key drivers of HCC angiogenesis. VEGF-targeting strategies already represent an important component of today's systemic treatment landscape of HCC, whereas targeting the Ang/Tie2 signaling pathway may harbor future potential in this context due to reported beneficial anticancer effects when targeting this pathway. In addition, a better understanding of the relation between Angs and HCC angiogenesis and progression may reveal their potential as predictive factors for post-treatment disease progression and prognosis. In this review, we give a comprehensive overview of the complex role of Ang/Tie2 signaling in HCC, pinpointing its potential value as biomarker and target for HCC treatments, aiding HCC diagnosis and therapy

Synthesis, in vitro and in vivo evaluation of 3β-[18F]fluorocholic acid for the detection of drug-induced cholestasis in mice

Introduction : Drug-induced cholestasis is a liver disorder that might be caused by interference of drugs with the hepatobiliary bile acid transporters. It is important to identify this interference early on in drug development. In this work, Positron Emission Tomography (PET)-imaging with a F-18 labeled bile acid analogue was introduced to detect disturbed hepatobiliary transport of bile acids. Methods : 3 beta-[F-18]fluorocholic acid ([F-18]FCA) was prepared by nucleophilic substitution of a mesylated precursor with [F-18]fluoride, followed by deprotection with sodium hydroxide. Transport of [F-18]FCA was assessed in vitro using CHO-NTCP, HEK-OATP1B1, HEK-OATP1B3 transfected cells and BSEP & MRP2 membrane vesicles. Investigation of [F-18]FCA metabolites was performed with primary mouse hepatocytes. Hepatobiliary transport of [F-18]FCA was evaluated in vivo in wild-type, rifampicin and bosentan pretreated FVB-mice by dynamic mu PET scanning. Results : Radiosynthesis of [F-18] FCA was achieved in a moderate radiochemical yield (8.11-1.94%; non-decay corrected; n = 10) and high radiochemical purity (>99%). FCA was transported by the basolateral bile acid uptake transporters NTCP, OATP1B1 and OATP1B3. For canalicular efflux, BSEP and MRP2 are the relevant bile acid transporters. [F-18]FCA was found to be metabolically stable. In vivo, [F-18]FCA showed fast hepatic uptake (4.5-0.5 min to reach 71.8-1.2% maximum % ID) and subsequent efflux to the gallbladder and intestines (93.3-6.0% ID after 1 hour). Hepatobiliary transport of [F-18]FCA was significantly inhibited by both rifampicin and bosentan. Conclusion : A F-18 labeled bile acid analogue, [F-18]FCA, has been developed that shows transport by NTCP, OATP, MRP2 and BSEP. [F-18]FCA can be used as a probe to monitor disturbed hepatobiliary transport in vivo and accumulation of bile acids in blood and liver during drug development

Rodent models of cholestatic liver disease : a practical guide for translational research

Cholestatic liver disease denotes any situation associated with impaired bile flow concomitant with a noxious bile acid accumulation in the liver and/or systemic circulation. Cholestatic liver disease can be subdivided into different types according to its clinical phenotype, such as biliary atresia, drug-induced cholestasis, gallstone liver disease, intrahepatic cholestasis of pregnancy, primary biliary cholangitis and primary sclerosing cholangitis. Considerable effort has been devoted to elucidating underlying mechanisms of cholestatic liver injuries and explore novel therapeutic and diagnostic strategies using animal models. Animal models employed according to their appropriate applicability domain herein play a crucial role. This review provides an overview of currently available in vivo animal models, fit-for-purpose in modelling different types of cholestatic liver diseases. Moreover, a practical guide and workflow is provided which can be used for translational research purposes, including all advantages and disadvantages of currently available in vivo animal models