Fatty acid synthase-positive hepatocytes and subsequent steatosis in rat livers by irinotecan

Sawano,Takeyuki; Shimizu,Takeshi; Yamada,Toshiyuki; Nanashima,Naoki; Miura,Takuya; Morohashi,Satoko; Kudo,Daisuke; Hui,Feng Mao; Kijima,Hiroshi; Hakamada,Kenichi; Tsuchida,Shigeki

doi:10.3892/or.2015.3814

Fatty acid synthase-positive hepatocytes and subsequent steatosis in rat livers by irinotecan

Authors:
- Takeyuki Sawano
- Takeshi Shimizu
- Toshiyuki Yamada
- Naoki Nanashima
- Takuya Miura
- Satoko Morohashi
- Daisuke Kudo
- Feng Mao Hui
- Hiroshi Kijima
- Kenichi Hakamada
- Shigeki Tsuchida
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Affiliations: Department of Gastroenterological Surgery, Hirosaki University Graduate School of Medicine, Hirosaki, Japan, Department of Biochemistry and Genome Biology, Hirosaki University Graduate School of Medicine, Hirosaki, Japan, Department of Medical Technology, Hirosaki University Graduate School of Health Sciences, Hirosaki, Japan, Department of Pathology and Bioscience, Hirosaki University Graduate School of Medicine, Hirosaki, Japan
Published online on: February 20, 2015 https://doi.org/10.3892/or.2015.3814
Pages: 2151-2160
Copyright: © Sawano et al. This is an open access article distributed under the terms of Creative Commons Attribution License [CC BY_NC 3.0].

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Abstract

Using a rat model, we investigated factors contributing to the pathogenesis of irinotecan-associated fatty liver disease. Male Sprague-Dawley rats were administered 200 mg/kg irinotecan by intraperitoneal injection on days 1-4, but not on days 5-7. This schedule was repeated 3 times. Rats were sacrificed 4, 18 and 25 days after the last injection, and liver steatosis was evaluated by hematoxylin and eosin (H&E) staining, microarray analysis and immunohistochemistry. Panacinar intrahepatocyte vacuoles were absent on days 4 and 25, but present on day 18, and this alteration was more prominent around the bile ducts than the central veins. Microarray analysis showed that the expression of genes involved in the synthesis of cholesterol and fatty acids was upregulated on day 4. Immunohistochemistry detected fatty acid synthase (Fasn)-strongly positive hepatocytes as well as the activation of liver progenitor cells on day 4, whereas intracellular vacuoles were evident in carbonic anhydrase 3 (CA3)-positive hepatocytes on day 18. Thus, irinotecan-induced liver steatosis was preceded by Fasn-strongly-positive hepatocytes and liver progenitor cell activation. The magnitude of the decrease in the number of Fasn-strongly positive hepatocytes between days 4 and 18 was similar to that of the increase in the number of CA3-positive hepatocytes accompanying vacuoles.

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