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

• Published in: Oncology reports Vol. 33; no. 5; pp. 2151 - 2160
• Main Authors: SAWANO, TAKEYUKI, SHIMIZU, TAKESHI, YAMADA, TOSHIYUKI, NANASHIMA, NAOKI, MIURA, TAKUYA, MOROHASHI, SATOKO, KUDO, DAISUKE, HUI, FENG MAO, KIJIMA, HIROSHI, HAKAMADA, KENICHI, TSUCHIDA, SHIGEKI
• Format: Journal Article
• Language: English
• Published: Greece D.A. Spandidos 01.05.2015; Spandidos Publications; Spandidos Publications UK Ltd
• Subjects: Animals; Antigens; Antineoplastic Agents, Phytogenic - adverse effects; Bile; Camptothecin - adverse effects; Camptothecin - analogs & derivatives; Cell cycle; Cell division; Chemokines; Chemotherapy; chemotherapy-associated steatohepatitis; Cholesterol; Colorectal cancer; Deoxyribonucleic acid; Development and progression; Disease Models, Animal; DNA; fatty acid synthase; Fatty Acid Synthases - biosynthesis; Fatty acids; Fatty liver; Fatty Liver - chemically induced; Fatty Liver - pathology; Genetic aspects; Hepatocytes - enzymology; Hepatocytes - pathology; Immunoglobulins; Immunohistochemistry; irinotecan; Kinases; Kupffer cell; Laboratory animals; Ligands; Lipid metabolism; Liver; Liver - pathology; liver progenitor cell; Male; Metabolism; Metabolites; Metastasis; Oligonucleotide Array Sequence Analysis; Pathogenesis; Polypeptides; Rats; Rats, Sprague-Dawley; Real-Time Polymerase Chain Reaction; Rodents; Transcription factors; United States > US; Japan
• ISSN: 1021-335X; 1791-2431
• DOI: 10.3892/or.2015.3814

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.