Abstract 83: A role of hepatic retinoid storage in diethynitrosamine-induced hepatic injury and hepatocarcinogenesis

Abstract

Abstract The liver is the main tissue site of retinoid (vitamin A and its derivatives) storage in the body and the non-parenchymal hepatic stellate cell (HSC) is the major cellular site of retinoid storage within the liver. Lipid droplets of HSCs contain a number of bioactive metabolites including retinoids. Following liver injury, HSCs undergo a process known as activation. Loss of retinyl esters, the retinoid storage form, and lipid droplets from HSCs is one of the first events in the development of hepatic disease, leading progressively to liver fibrosis, cirrhosis and hepatocellular carcinoma (HCC). Although the loss of lipid droplets is a hallmark of HSC activation, whether it is a cause or consequence of the HSC activation process is unclear. Moreover, the contribution of the loss of hepatic retinoid storage to hepatic injury and hepatocarcinogenesis remains unknown. To investigate the role of hepatic retinoid storage and retinoid-containing lipid droplets in hepatic injury and hepatocarcingenesis, we studied diethynitrosamine (DEN)-induced HCC in lecithin:retinol acyltransferase (LRAT) knockout (KO) mice, which lack retinoid-containing lipid droplets in their HSCs, and in retinol-binding protein (RBP) KO mice, which are unable to mobilize hepatic retinoid stores. We measured a number of factors implicated in hepatic injury and cancer initiation. Using an acute hepatic injury model for investigating cancer initiation, assessment of mRNA levels by qRT-PCR of TNF alpha and TGF beta in livers of LRAT KO mice indicated that these mice were more susceptible to cancer initiation than WT mice. On the other hand RBP KO mice showed less susceptibility. LRAT KO mice showed higher levels of CYP26A1, a gene whose expression is known to be highly and directly responsive to retinoic acid level, suggesting that hepatic retinoic acid levels in LRAT KO mice were higher than that of WT, and that this may influence hepatic injury and carcinogenesis. Overall, our data suggest that hepatic retinoid storage can influence the progression of hepatic disease. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 83.