Abstract
Non-alcoholic fatty liver disease has become one of the most common causes of chronic liver disease that can develop into a more serious form, non-alcoholic steatohepatitis, leading to liver cirrhosis and hepatocellular carcinoma. Although hepatic retinoid stores are progressively lost during the development of liver disease, how this affects steatohepatitis and its related hepatocarcinogenesis is unknown. In order to investigate these, we used subcutaneous injection of streptozotocin (0.2 mg/body) and high-fat diet to induce steatohepatitis and hepatic tumorigenesis in lecithin:retinol acyltransferase -deficient mice (n = 10), which lack stored retinoid in the liver, and control mice (n = 12). At the termination of the experiment (16 weeks of age), the development of hepatic tumors was significantly suppressed in mutant mice compared to controls. Lower serum levels of alanine aminotransferase and decreased hepatic levels of cyclin D1 were observed in mutant mice. Mutant mice exhibited increased levels of retinoic acid-responsive genes, including p21, and decreased oxidative stress as evaluated by serum and liver markers. Our findings are consistent with the conclusion that mutant mice are less susceptible to steatohepatitis-related liver tumorigenesis due to increased retinoid signaling, which is accompanied by up-regulated p21 expression and attenuated oxidative stress.
Highlights
Non-alcoholic fatty liver disease (NAFLD) is characterized by a broad spectrum of disease forms, ranging from simple fatty liver through non-alcoholic steatohepatitis (NASH), involving chronic inflammation of the liver and increased risk of development of liver fibrosis, cirrhosis, and hepatocellular carcinoma (HCC) [1]
We examined the effects of endogenous hepatic stellate cell (HSC) retinoid stores and activation of retinoid signaling on NASH and liver tumor development in wild-type and Lrat KO mice that were administered streptozotocin (STZ) and fed a high-fat diet (HFD) to induce NASH and HCC
NAFLD/NASH is a serious health issue worldwide since NASH can progress to liver cirrhosis and cause HCC [24]
Summary
Non-alcoholic fatty liver disease (NAFLD) is characterized by a broad spectrum of disease forms, ranging from simple fatty liver through non-alcoholic steatohepatitis (NASH), involving chronic inflammation of the liver and increased risk of development of liver fibrosis, cirrhosis, and hepatocellular carcinoma (HCC) [1]. The clinical importance of NAFLD is illustrated by its high prevalence (6.3–33%, with a median of 20%) in the general population [2] and is associated with increased liver-related mortality and HCC [3]. A number of studies have indicated that the presence of insulin resistance and increased oxidative stress are associated with the progression of NAFLD/ NASH [4, 5]. Other factors are important for the development and progression of NAFLD/ NASH, including genetic polymorphisms, adipocytokine www.impactjournals.com/oncotarget Mice No of mice Incidence (%) Adenoma HCC Control LRAT KO.
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