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Disrupted regulation and accumulation of bile salts (BS) in the liver can contribute towards progressive liver damage and fibrosis. Here, we investigated the role of BS in the progression of cholestatic injury and liver fibrosis using 3D scaffold-free multicellular human liver microtissues (MTs) comprising the cell lines HepaRG, THP-1 and hTERT-HSCs. This in vitro model has been shown to recapitulate cellular events leading to fibrosis including hepatocellular injury, inflammation and activation of HSCs, ultimately leading to increased deposition of extracellular matrix (ECM). In order to better differentiate the contribution of individual cells during cholestasis, the effects of BS were evaluated either on each of the three cell types individually or on the multicellular MTs. Our data corroborate the toxic effects of BS on HepaRG cells and indicate that BS exposure elicited a slight increase in cytokines without causing stellate cell activation. Contrarily, using the MTs, we could demonstrate that low concentrations of BS led to cellular damage and triggered a fibrotic response. This indicates that cellular interplay is required to achieve BS-triggered activation of HSC. Moreover, BS were capable of down-regulating CYP7A1 expression in MTs and elicited abnormal lipid production (accumulation) concordant with clinical cases where chronic cholestasis results in hypercholesterolemia.
This article was published in the following journal.
Name: Toxicology in vitro : an international journal published in association with BIBRA
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Cholestanes substituted in any position with one or more hydroxy groups. They are found in feces and bile. In contrast to bile acids and salts, they are not reabsorbed.
The response of cells in sensing a difference in OSMOTIC PRESSURE between the inside and outside of the cell. This response includes signaling from osmotic sensors to activate transcription factors, which in turn regulate the expression of osmocompensatory genes, all functioning to maintain CELL VOLUME and the water concentration inside the cells.
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