Abstract 5555: Diethylnitrosamine-induced hepatic injury and hepatocarcinogenesis: A role for hepatic retinoids

Abstract

Abstract The liver is the main tissue site of retinoid storage in the body and the non-parenchymal hepatic stellate cell (HSC) is the major cellular site of retinoid storage within the liver. Loss of retinoid-containing lipid droplets (LDs) from HSCs is one of the first events in the development of hepatic diseases, leading progressively to liver fibrosis, cirrhosis and hepatocellular carcinoma. Although the loss of LDs is a hallmark of HSC activation, the contribution of hepatic retinoid storage to hepatic injury and hepatocarcinogenesis remains unknown. Lecithin:retinol acyltransferase (LRAT) is the sole enzyme responsible for storing hepatic retinoid and LRAT knockout (KO) mice lack liver retinoid stores. Retinol-binding protein (RBP) is the principal transport protein for retinol in the blood. RBP KO mice are unable to mobilize hepatic retinoid stores and have significantly more retinoid storage in the liver compared to wild type (WT) mice. In this study, we investigated the effects of endogenous retinoids on hepatic injury and hepatocarcinogenesis. We induced hepatic injury and HCC using diethylnitrosamine (DEN) in WT, LRAT KO and RBP KO mice. Both acute (for 24 and 48 hours after DEN administration) and long-term (for 8 months after DEN administration) studies were undertaken. After DEN injection of WT, LRAT KO, and RBP KO mice, serum levels of alanine transaminase (ALT) were significantly lower and Cyclin D1 and Ki-67 mRNA expression levels were decreased in the livers of the KOs compared to WT mice. This suggests that LRAT KO and RBP KO mice are less susceptible to DEN-induced liver injury and following compensatory proliferation. Furthermore, 8-month-old DEN-treated LRAT KO (n = 18) and RBP KO (n = 13) mice showed lower HCC incidence, fewer tumors, and smaller tumors than DEN-treated WT mice (n = 24). Five-month-old male LRAT KO and RBP KO mice showed higher expression levels of retinoic acid (RA) responsive genes, such as Cyp26A1 and RARβ, mRNA in their liver compared to WT, indicating that RA signaling is upregulated in the livers of the KOs’ mice. The expression levels of p21 mRNA in LRAT KO and RBP KO mice liver were higher than WT at several time points in both acute and long-term studies. Together these results suggest that increased RA signaling and associated higher p21 expression play important roles in the lower susceptibility of these mouse models to liver injury and hepatocarcinogenesis. We are presently investigating other possibilities that the presence/absence through which endogenous hepatic retinoids might have effects on hepatic diseases, probably by modulating several cancer signaling pathways, regulating apoptosis of hepatocytes and cancer cells, or influencing the tumor-surrounding microenvironment. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 5555. doi:10.1158/1538-7445.AM2011-5555