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B-13 progenitor-derived hepatocytes (B-13/H cells) model lipid dysregulation in response to drugs and chemicals

Lookup NU author(s): Dr Alistair Leitch, Philip Probert, Dr Stephanie Meyer, Professor George Kass, Professor Matthew Wright

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This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).

Abstract

© 2017 The Authors. Lipid dysregulation is a common hepatic adverse outcome after exposure to toxic drugs and chemicals. A donor-free rat hepatocyte-like (B-13/H) cell was therefore examined as an in vitro model for investigating mechanisms. The B-13/H cell irreversibly accumulated triglycerides (steatosis) in a time- and dose-dependent manner when exposed to fatty acids, an effect that was potentiated by the combined addition of hyperglycaemic levels of glucose and insulin. B-13/H cells also expressed the LXR nuclear receptors and exposure to their activators - T0901317 or GW3965 - induced luciferase expression from a transfected LXR-regulated reporter gene construct and steatosis in a dose-dependent manner with T0901317. Exposing B-13/H cells to a variety of cationic amphiphilic drugs - but not other hepatotoxins - also resulted in a time- and dose-dependent accumulation of phospholipids (phospholipidosis), an effect that was reduced by over-expression of lysosomal phospholipase A2. Through application of this model, hepatotoxin methapyrilene exposure was shown to induce phospholipidosis in both B-13 and B-13/H cells in a time- and dose-dependent manner. However, methapyrilene was only toxic to B-13/H cells and inhibitors of hepatotoxicity enhanced phospholipidosis, suggesting phospholipidosis is not a pathway in toxicity for this withdrawn drug. In contrast, pre-existing steatosis had minimal effect on methapyrilene hepatotoxicity in B-13/H cells. These data demonstrate that the donor free B-13 cell system for generating hepatocyte-like cells may be employed in studies of fatty acid- and LXR activator-induced steatosis and phospholipidosis and in the dissection of pathways leading to adverse outcomes such as hepatotoxicity.

Publication metadata

Author(s): Leitch AC, Probert PME, Shayman JA, Meyer SK, Kass GEN, Wright MC

Publication type: Article

Publication status: Published

Journal: Toxicology

Year: 2017

Volume: 386

Pages: 120-132

Print publication date: 01/07/2017

Online publication date: 26/05/2017

Acceptance date: 23/05/2017

Date deposited: 28/06/2017

ISSN (print): 0300-483X

ISSN (electronic): 1879-3185

Publisher: Elsevier Ireland Ltd

URL: https://doi.org/10.1016/j.tox.2017.05.014

DOI: 10.1016/j.tox.2017.05.014

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