SAT008 Elucidating The Role Of Small Heterodimer Partner In Injury Associated Hepatic Proliferation

Abstract

Abstract Disclosure: R.P. Shaw: None. Small Heterodimer Partner (SHP) is an atypical nuclear receptor that is involved in the regulation of several metabolic pathways but lacks the typically conserved DNA binding domain seen in other nuclear receptors. Several studies have found that SHP expression is drastically lower due to epigenetic silencing in human hepatocellular carcinoma (HCC), the fourth most fatal cancer worldwide, indicating a crucial role for SHP in controlling liver proliferation. SHP can modulate the cell cycle by inhibiting cyclin D1, and remarkably, SHP knockout mice develop tumours at 12 to 15 months of age. The underlying mechanism(s) of this tumorigenesis may be consequential to increases in cyclin D1, yes associated protein (YAP), and decreases in apoptosis when SHP expression is reduced. Furthermore, excessive bile acid (BA) levels in cholestatic liver diseases are cytotoxic and in large quantities, can induce hepatic injury and subsequent hepatic proliferation. We have confirmed that in male mice, loss of hepatic SHP leads to increased systemic BA levels, suggesting these mice may also have increased hepatic injury and proliferation. Moreover, BAs have been identified as upstream regulators of YAP. YAP is a transcriptional coactivator that regulates genes involved in cellular proliferation and differentiation and is also overexpressed in hepatic cancers. In addition to BAs, YAP has also been shown to be activated upon treatment with 0.1% DDC (3,5-Diethoxycarbonyl-1,4-Dihydrocollidine) diet, a chemical-based biliary injury model. We have recently demonstrated that male LSHPKO mice exhibit significantly increased hepatic proliferation, inflammation, and cyclin B1 & B2 mRNA expression in response to the DDC challenge. We have also characterized apoptotic pathways and cell death using TUNEL staining in these mice and characterized how the downregulation of YAP in LSHPKO mice affects hepatic proliferation. These results, in tandem with previous studies of YAP, suggest that hepatic SHP may play a role in mediating hepatic proliferation after injury. It is possible that SHP may act as a repressor for YAP-mediated function. Presentation: Saturday, June 17, 2023