| Hepatocytes |
NTCP (SLC10A1): Na+-driven BA entry into cells, deficiency or inhibition results in hypercholemia without cholestatic injury |
Human and rodent cell cultures, animal models, and human subjects |
(11-13) |
| BSEP (ABCB11): ATP-dependent BA excretion against concentration gradient, deficiency leads to parenchymal cell death |
Animal models and human subjects |
(14,15) |
| FXR (NR1H4): BA nuclear receptor, activation may reduce NFκB mediated hepatic inflammation |
Human and rodent cell cultures, animal models |
(16-18) |
| EGR1: a transcription factor stimulates the expression of inflammatory genes, KO in mice reduces cholestatic liver injury |
Mouse cell cultures, BDL mouse model |
(19,20) |
| TLR9: cell signaling responds to mitochondrial damage and ER-stress, triggers inflammatory response by stimulating chemokine expression |
Mouse cell cultures, BDL mouse model |
(13,21) |
| NFAT: cell signaling responds to Ca2+ dys-regulation, triggers inflammatory response by stimulating the expression of inflammatory genes |
Mouse and human cell cultures, cholestatic mouse models, patients with PBC or PSC |
(22) |
| Acute bile duct obstruction causes bile lumen rupture, bile leak and results in cytolytic toxic injury |
Animal models and human subjects |
(23) |
| RIPKs and MLKL: mediated via TNFa, activated by DAMPs release from necrotic and necroptotic cell death |
Animal models and human subjects |
(24,25) |
| Cholangiocytes |
OSTα-OSTβ: efflux of intracellular BA to blood, protect bile duct from BA overload, deficiency in humans developed bile duct injury and fibrosis |
Human subjects. |
(26,27) |
| TGR5: BA membrane receptor, activation of cAMP signaling, leading to cell proliferation, deficiency aggravate cholestatic injury |
Animal models and patients with PBC or PSC |
(28,29) |
| S1PR2: activated by TCA, release of exosomal H19 to mediate inflammation, stimulates bile duct proliferation |
Cell cultures, animal models, and patients with PBC or PSC |
(30-32) |
| Stellate cells |
TGR5: BA membrane receptor, activation leads to cell proliferation |
Rat stellate cell cultures and human LX-2 cells |
(33,34) |
| Kupffer cells |
TGR5: BA membrane receptor, activation represses LPS stimulated cytokine expression; inflammasomes: exacerbates cholestatic liver injury but bile acids do not directly activate the inflammasome |
Mouse cell cultures, BDL mouse model, patient with PBC or PSC |
(35,36) |
| NKT cells |
FXR: activation represses the production of osteopontin, a proinflammatory mediator |
Mouse cell cultures, and mouse hepatitis model |
(37) |
