title: Plasma lipid profiling of different types of hepatic fibrosis induced by carbon tetrachloride and lomustine in rats.
abstract: BACKGROUND
  Plasma lipid profiling has emerged as a useful tool for understanding the pathophysiology of hepatic injury and disease. Hepatic fibrosis results from chronic, progressive damage to the liver and can lead, in turn, to more serious conditions such as hepatic cirrhosis and hepatocellular carcinoma. Thus, the present study aimed to investigate the plasma lipid profiles of two types of hepatic fibrosis in order to aid the understanding of the pathophysiology of hepatic fibrosis.
  
  
  METHODS
  A liquid chromatography and mass spectrometry platform was used to reveal and compare the plasma lipid profiles of two types of chemical-induced hepatic fibrosis. Rat models of centrilobular fibrosis and bile duct fibrosis were established via chronic exposure to the known fibrogenic hepatotoxins, carbon tetrachloride (CCl4) or lomustine (LS), respectively, over a 28-day period. To delineate the specific alterations in the lipid profiles as a result of the hepatic fibrosis, we also employed non-fibrogenic hepatotoxicants (2-acetamidofluorene, N-nitrosodiethylamine, and ethambutol) as well as 3-day treatment of CCl4 and LS, which did not induce fibrosis.
  
  
  RESULTS
  Our assay platform identified 228 lipids in the rat plasma, and the global lipid profile clearly distinguished these models from the control via principal component analysis. In addition, the alteration of the plasma lipid profile caused by CCl4 and LS were clearly different. Furthermore, a number of lipids were identified as specific alterations caused by fibrosis induced only by CCl4 and LS, respectively. Three lysophosphatidylcholines (LPC[18:3], LPC[20:4], and LPC[22:6]), and three phosphatidylcholines (PC[18:2/20:4], PC[40:8], and PC[20:4/22:6]) are specific circulating lipids, the levels of which were altered by both CCl4 and LS treatment; however, their levels were decreased by chronic exposure to CCl4 and increased by chronic exposure to LS.
  
  
  CONCLUSIONS
  These results suggest that different types of chemical-induced hepatic fibrosis demonstrate clear differences in their plasma lipid profiles. Our study provides insights into the alteration of plasma lipidomic profiles as a result of the fibrosis of different parts of the hepatic lobule, and may help to understand the pathophysiology of different types of hepatic fibrosis.
authors.affiliation: Division of Medical Safety Science, National Institute of Health Sciences, 1-18-1 Kamiyoga, Setagaya, Tokyo, 158-8501, Japan.
authors.forename: Masaki
authors.initials: M
authors.lastname: Ishikawa
authors.affiliation: Division of Medical Safety Science, National Institute of Health Sciences, 1-18-1 Kamiyoga, Setagaya, Tokyo, 158-8501, Japan. saitok2@nihs.go.jp.
authors.forename: Kosuke
authors.initials: K
authors.lastname: Saito
authors.affiliation: Toxicogenomics Informatics Project, National Institutes of Biomedical Innovation, Health and Nutrition, 7-6-8 Saitoazagi, Ibaraki, Osaka, 567-0085, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Yamada
authors.affiliation: Toxicogenomics Informatics Project, National Institutes of Biomedical Innovation, Health and Nutrition, 7-6-8 Saitoazagi, Ibaraki, Osaka, 567-0085, Japan.
authors.forename: Noriyuki
authors.initials: N
authors.lastname: Nakatsu
authors.affiliation: Division of Medical Safety Science, National Institute of Health Sciences, 1-18-1 Kamiyoga, Setagaya, Tokyo, 158-8501, Japan.
authors.forename: Keiko
authors.initials: K
authors.lastname: Maekawa
authors.affiliation: Division of Medical Safety Science, National Institute of Health Sciences, 1-18-1 Kamiyoga, Setagaya, Tokyo, 158-8501, Japan.
authors.forename: Yoshiro
authors.initials: Y
authors.lastname: Saito
mesh_terms: D000818:Animals; D002251:Carbon Tetrachloride / Q000633:toxicity*; D008055:Lipids / Q000097:blood* / Q000737:chemistry; D008099:Liver / Q000187:drug effects / Q000473:pathology; D008103:Liver Cirrhosis / Q000097:blood* / Q000139:chemically induced* / Q000473:pathology; D008130:Lomustine / Q000633:toxicity*; D008297:Male; D017207:Rats, Sprague-Dawley
chemical_list: D008055:Lipids; D008130:Lomustine; D002251:Carbon Tetrachloride
keywords: Hepatic fibrosis; Hepatotoxicity; LC/MS, lipidomics; Plasma lipid profiling