title: Fatty acid synthase-positive hepatocytes and subsequent steatosis in rat livers by irinotecan.
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.
authors.affiliation: Department of Gastroenterological Surgery, Hirosaki University Graduate School of Medicine, Hirosaki, Japan.
authors.forename: Takeyuki
authors.initials: T
authors.lastname: Sawano
authors.affiliation: Department of Biochemistry and Genome Biology, Hirosaki University Graduate School of Medicine, Hirosaki, Japan.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Shimizu
authors.affiliation: Department of Biochemistry and Genome Biology, Hirosaki University Graduate School of Medicine, Hirosaki, Japan.
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Yamada
authors.affiliation: Department of Medical Technology, Hirosaki University Graduate School of Health Sciences, Hirosaki, Japan.
authors.forename: Naoki
authors.initials: N
authors.lastname: Nanashima
authors.affiliation: Department of Gastroenterological Surgery, Hirosaki University Graduate School of Medicine, Hirosaki, Japan.
authors.forename: Takuya
authors.initials: T
authors.lastname: Miura
authors.affiliation: Department of Pathology and Bioscience, Hirosaki University Graduate School of Medicine, Hirosaki, Japan.
authors.forename: Satoko
authors.initials: S
authors.lastname: Morohashi
authors.affiliation: Department of Gastroenterological Surgery, Hirosaki University Graduate School of Medicine, Hirosaki, Japan.
authors.forename: Daisuke
authors.initials: D
authors.lastname: Kudo
authors.affiliation: Department of Gastroenterological Surgery, Hirosaki University Graduate School of Medicine, Hirosaki, Japan.
authors.forename: Feng Mao
authors.initials: FM
authors.lastname: Hui
authors.affiliation: Department of Pathology and Bioscience, Hirosaki University Graduate School of Medicine, Hirosaki, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Kijima
authors.affiliation: Department of Gastroenterological Surgery, Hirosaki University Graduate School of Medicine, Hirosaki, Japan.
authors.forename: Kenichi
authors.initials: K
authors.lastname: Hakamada
authors.affiliation: Department of Biochemistry and Genome Biology, Hirosaki University Graduate School of Medicine, Hirosaki, Japan.
authors.forename: Shigeki
authors.initials: S
authors.lastname: Tsuchida
mesh_terms: D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000009:adverse effects; D002166:Camptothecin / Q000009:adverse effects / Q000031:analogs & derivatives*; D004195:Disease Models, Animal; D064429:Fatty Acid Synthases / Q000096:biosynthesis*; D005234:Fatty Liver / Q000139:chemically induced* / Q000473:pathology; D022781:Hepatocytes / Q000201:enzymology* / Q000473:pathology; D007150:Immunohistochemistry; D000077146:Irinotecan; D008099:Liver / Q000473:pathology; D008297:Male; D020411:Oligonucleotide Array Sequence Analysis; D051381:Rats; D017207:Rats, Sprague-Dawley; D060888:Real-Time Polymerase Chain Reaction
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D000077146:Irinotecan; D064429:Fatty Acid Synthases; D002166:Camptothecin