ABSTRACT
Primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC), the most common types of cholestatic liver disease (CLD), result in enterohepatic obstruction, bile acid accumulation, and hepatotoxicity. The mechanisms by which hepatocytes respond to and cope with CLD remain largely unexplored. This study includes the characterization of hepatocytes isolated from explanted livers of patients with PBC and PSC. We examined the expression of hepatocyte-specific genes, intracellular bile acid (BA) levels, and oxidative stress in primary-human-hepatocytes (PHHs) isolated from explanted livers of patients with PBC and PSC and compared them with control normal human hepatocytes. Our findings provide valuable initial insights into the hepatocellular response to cholestasis in CLD and help support the use of PHHs as an experimental tool for these diseases.
GRAPHICAL ABSTRACT
Disclosure statement
A.S.‐G is an inventor on a patent application that describes the use of transcription factors in treating chronic liver failure (US20140249209). E.N.T. and A.S.‐G. are inventors of a provisional patent application related to methods to enhance hepatic functions in human failing livers (PCT/US2020/055500). A.S.‐G. is a co‐founder and has a financial interest in Von Baer Wolff, Inc. a company focused on biofabrication of autologous human hepatocytes from stem cells technology. A.S.‐G. and A.O. are co‐founders and have a financial interest in Pittsburgh ReLiver Inc, a company focused on reprogramming hepatocytes in liver failure. All interests are managed by the Conflict of Interest Office at the University of Pittsburgh in accordance with their policies.
Supplementary material
Supplemental data for this article can be accessed online at https://doi.org/10.1080/15476278.2023.2247576
Abbreviations
CLD | = | Cholestatic Liver Disease |
PBC | = | Primary Biliary Cholangitis |
PSC | = | Primary Sclerosing Cholangitis |
UDCA | = | Ursodeoxycholic Acid |
BA | = | Bile Acid |
ESLD | = | End-stage Liver Disease |
PHH | = | Primary Human Hepatocyte |
FBS | = | Fetal Bovine Serum |
Npcs | = | Non-Parenchymal Cells |
HNF4α | = | Hepatocyte Nuclear Factor 4 Alpha |
CYP7A1 | = | Cholesterol 7 Alpha-Hydroxylase |
Pparα | = | Peroxisome Proliferator-Activated Receptor-Alpha |
PXR | = | Pregnane X Receptor |
FXR | = | Farnesoid X Receptor |
LXR | = | Liver X Receptor |
UGT1A1 | = | UDP-Glucuronosyltransferase 1–1 |
NRF2 | = | Nuclear Factor Erythroid 2–Related Factor 2 |
GPX4 | = | Glutathione Peroxidase 4 |
CAR | = | Chimeric Antigen Receptor |
MDR1 | = | Multidrug Resistance 1 |
MDR3 | = | Multidrug Resistance 3 |
MRP2 | = | Multidrug Resistance-Associated Protein 2 |
BSEP | = | Bile Salt Export Pump |
NTCP | = | Na+ -Taurocholate Cotransporting Polypeptide |