Abstract 5240: Lacking hepatic retinoid storage in mice suppresses NASH-related hepatocarcinogenesis

Abstract

Abstract Non-alcoholic fatty liver disease (NAFLD), which is strongly associated with metabolic syndrome, has become one of the most common causes of chronic liver disease in developed countries. Some patients with NAFLD develop a more serious form of the disease, non-alcoholic steatohepatitis (NASH), and NASH can develop cirrhosis or even hepatocellular carcinoma (HCC). Although hepatic retinoid (vitamin A) stores are progressively lost during the development of liver diseases, how this affects NAFLD/NASH and NASH-related hepatocarcinogenesis is unknown. In order to investigate this, we used streptozotocin (STZ) and high-fat diet (HFD) to induce NASH and related hepatic tumorigenesis in matched wild-type and lecithin:retinol acyltransferase (LRAT) knockout (KO) mice, which lack stored retinoid in the liver. LRAT is the sole enzyme responsible for hepatic retinyl ester synthesis since LRAT KO mice completely lack lipid droplets in hepatic stellate cells. Mice were injected with STZ within 48 hours after birth and then fed HFD from 4 to 16 weeks of age. At the termination of the experiment, liver tumors were observed macroscopically and microscopically in both groups. In LRAT KO mice, the development of hepatic adenoma and HCC was significantly suppressed compared to control group. LRAT KO mice showed decreased expression levels of cyclin D1 and TGF-beta mRNA in the liver. The serum levels of d-ROMs and BAP were measured and the d-ROM/BAP ratio, which indicates oxidative stress, markedly decreased in LRAT KO mice. The fibrosis in the liver of the LRAT KO mice was decreased. In addition, liver fibrosis in LRAT KO mice was suppressed. These findings indicate that LRAT KO mice are less susceptible to STZ and HFD-induced liver tumorigenesis due to regulation of cell cycle and attenuation of oxidative stress. The amount of hepatic retinoid may affect the progression of NASH and the development of NASH-related HCC. Citation Format: Takayasu Ideta, Yohei Shirakami, Tsuneyuki Miyazaki, Hiroyasu Sakai, Takuji Tanaka, William S. Blaner, Masahito Shimizu. Lacking hepatic retinoid storage in mice suppresses NASH-related hepatocarcinogenesis. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 5240.