Oncotarget

Research Papers:

Non-alcoholic steatohepatitis-related liver tumorigenesis is suppressed in mice lacking hepatic retinoid storage

Takayasu Ideta, Yohei Shirakami _, Masaya Ohnishi, Akinori Maruta, Koki Obara, Tsuneyuki Miyazaki, Takahiro Kochi, Hiroyasu Sakai, Hiroyuki Tomita, Takuji Tanaka, William S. Blaner and Masahito Shimizu

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Oncotarget. 2017; 8:70695-70706. https://doi.org/10.18632/oncotarget.19978

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Abstract

Takayasu Ideta1, Yohei Shirakami1,2, Masaya Ohnishi1, Akinori Maruta1, Koki Obara1, Tsuneyuki Miyazaki1, Takahiro Kochi1, Hiroyasu Sakai1, Hiroyuki Tomita3, Takuji Tanaka4, William S. Blaner5 and Masahito Shimizu1

1Department of Gastroenterology, Gifu University Graduate School of Medicine, Gifu, Japan

2Department of Informative Clinical Medicine, Gifu University Graduate School of Medicine, Gifu, Japan

3Department of Tumor Pathology, Gifu University Graduate School of Medicine, Gifu, Japan

4Division of Pathology, Gifu Municipal Hospital, Gifu, Japan

5Department of Medicine, Columbia University, New York, NY, USA

Correspondence to:

Yohei Shirakami, email: [email protected]

Keywords: retinoid, hepatocellular carcinoma (HCC), non-alcoholic steatohepatitis (NASH), lecithin:retinol acyltransferase (LRAT), oxidative stress

Received: January 04, 2017    Accepted: July 18, 2017    Published: August 07, 2017

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.


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