title: Potential of (99m)Tc-MIBI SPECT imaging for evaluating non-alcoholic steatohepatitis induced by methionine-choline-deficient diet in mice.
abstract: BACKGROUND
  Hepatic mitochondrial dysfunction has been implicated in pathological conditions leading to non-alcoholic steatohepatitis (NASH). Technetium-99 m-2-methoxyisobutyl-isonitrile ((99m)Tc-MIBI), a lipophilic cationic myocardial perfusion agent, is retained in the mitochondria depending on membrane potential. The aim of this study was to investigate the feasibility of (99m)Tc-MIBI for evaluating the hepatic mitochondrial dysfunction induced by methionine-choline-deficient (MCD) diet in mice.
  
  
  METHODS
  Male C57Black6J/jcl mice were fed a MCD diet for up to 4 weeks. SPECT scan (N =6) with (99m)Tc-MIBI was performed at 2 and 4 weeks after MCD diet. Mice were imaged with small-animal SPECT/CT under isoflurane anesthesia. Radioactivity concentrations of the liver were measured, and the time of maximum (T max) and the elimination half-life (T 1/2) were evaluated. After SPECT scan, liver histopathology was analyzed to evaluate steatosis and inflammation. Non-alcoholic fatty liver disease (NAFLD) activity score was obtained from the histological score of hepatic steatosis and inflammation. Blood biochemistry and hepatic ATP content were also measured (N =5 to 6).
  
  
  RESULTS
  Plasma alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels were significantly elevated at 2 and 4 weeks after MCD diet. A decrease in hepatic ATP content was also observed in MCD-fed mice. (99m)Tc-MIBI SPECT imaging clearly showed the decrease of hepatic (99m)Tc-MIBI retention in MCD-fed mice compared to control mice. T 1/2 after (99m)Tc-MIBI injection was significantly decreased in the liver of MCD-fed mice (control, MCD 2 weeks, and MCD 4 weeks, T 1/2 = 57.6, 37.6, and 19.8 min, respectively), although no change in T max was observed in MCD-fed mice. SPECT data and histological score showed that the negative correlation (r = -0.74, p <0.05) between T 1/2 and NAFLD activity score was significant.
  
  
  CONCLUSIONS
  Hepatic (99m)Tc-MIBI elimination was increased with increase in NAFLD activity score (NAS) in mice fed MCD diet for 2 and 4 weeks. These results suggest that (99m)Tc-MIBI SPECT imaging might be useful for detecting hepatic mitochondrial dysfunction induced by steatosis and inflammation such as NAFLD or NASH.
authors.affiliation: Department of Drug Metabolism and Pharmacokinetics, Research Laboratory for Development, Shionogi & Co., Ltd., 3-1-1, Futaba-cho, Toyonaka, Osaka, 561-0825, Japan, takemi.rokugawa@shionogi.co.jp.
authors.forename: Takemi
authors.initials: T
authors.lastname: Rokugawa
authors.forename: Tomoya
authors.initials: T
authors.lastname: Uehara
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Higaki
authors.forename: Shuuichi
authors.initials: S
authors.lastname: Matsushima
authors.forename: Atsushi
authors.initials: A
authors.lastname: Obata
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Arano
authors.forename: Kohji
authors.initials: K
authors.lastname: Abe