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Hepatocytotoxicity leads to Sustained proliferation
Key Event Relationship Overview
AOPs Referencing Relationship
Life Stage Applicability
Key Event Relationship Description
Hepatocytes are typically quiescent, with only about 1-2% turnover. However, under cytotoxic conditions, the liver has a remarkable ability to replace dead or dying cells through induction of cellular proliferation to create new liver cells and maintain homeostasis. Indeed, following surgical resection or chemically induced injury, the liver is able to activate cell division and regenerate itself.
The liver replaces dead cells via two main pathways: (1) hypertrophy and division of existing cells; or (2) proliferation of a population of facultative stem cells, called biliary epithelial cells (BECs), located at the Canals of Hering (in zone 1 where canaliculi join and drain into the main bile duct). Facultative stem cells are functional, differentiated cells that will dedifferentiate in response to tissue damage, thereby becoming a population of progenitor cells that can redifferentiate to replace multiple lost cell types. In a process known as ductal expansion, BECs dedifferentiate into oval cells, which then redifferentiate into hepatocytes or BECs in order to regenerate damaged liver tissue. Liver cell proiferattion and regeneration has been extensively reviewed (Mao, et al. 2014, Stanger 2015, Yanger and Stanger 2011).
On a molecular level, how liver cell proliferation occurs is less completely understood. Molecular signals that are released from dying cells trigger proliferation of existing cells. Important players include the transcription factors AP-1 (particularly the c-Jun monomer) and NF-kappaB, both of which are not normally expressed in adult liver, but are up-regulated following partial hepatectomy and are required for hepatic regeneration.
Liver cellular proliferation has been well studied in mice, rats, and zebrafish (Cox and Goessling 2015, Goessling and Sadler 2015), which are all systems that are thought to work in a similar way to human livers (Kwon, et al. 2015). Liver regeneration can be observed following partial hepatectomy. Methods for 2/3 partial hepatectomy have been described (Mitchell and Willenbring 2008, Mitchell and Willenbring 2014).
Evidence Collection Strategy
Evidence Supporting this KER
Strong. The liver is well known to regenerate itself following chemical or surgical injury. It is widely accepted that significant cytotoxicity to the liver leads to cellular proliferation (Forbes and Newsome 2016). If this occurs during chronic exposure these effects would persist or be sustained.
Uncertainties and Inconsistencies
We are not aware of any instance in which significant amounts of hepatotoxicity (in genetically normal livers) would not lead to cellular proliferation.
Known modulating factors
This KER is relevant for sustained or persistent exposures.
Known Feedforward/Feedback loops influencing this KER
Domain of Applicability
Relevant to any species with a liver.
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