Abstract
BackgroundHepatic mitochondrial dysfunction has been implicated in pathological conditions leading to non-alcoholic steatohepatitis (NASH). Technetium-99 m-2-methoxyisobutyl-isonitrile (99mTc-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 99mTc-MIBI for evaluating the hepatic mitochondrial dysfunction induced by methionine-choline-deficient (MCD) diet in mice.MethodsMale C57Black6J/jcl mice were fed a MCD diet for up to 4 weeks. SPECT scan (N =6) with 99mTc-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 (Tmax) and the elimination half-life (T1/2) 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).ResultsPlasma 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. 99mTc-MIBI SPECT imaging clearly showed the decrease of hepatic 99mTc-MIBI retention in MCD-fed mice compared to control mice. T1/2 after 99mTc-MIBI injection was significantly decreased in the liver of MCD-fed mice (control, MCD 2 weeks, and MCD 4 weeks, T1/2 = 57.6, 37.6, and 19.8 min, respectively), although no change in Tmax was observed in MCD-fed mice. SPECT data and histological score showed that the negative correlation (r = −0.74, p <0.05) between T1/2 and NAFLD activity score was significant.ConclusionsHepatic 99mTc-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 99mTc-MIBI SPECT imaging might be useful for detecting hepatic mitochondrial dysfunction induced by steatosis and inflammation such as NAFLD or NASH.
Highlights
Hepatic mitochondrial dysfunction has been implicated in pathological conditions leading to non-alcoholic steatohepatitis (NASH)
Non-alcoholic fatty liver disease (NAFLD) encompasses a wide spectrum of conditions ranging from simple steatosis to non-alcoholic steatohepatitis (NASH) with or without fibrosis, cirrhosis, and hepatocellular carcinoma [2]
Hepatic ATP content Hepatic ATP was significantly decreased in mice fed MCD diet for 2 weeks (2.57 ± 0.03 μmol/g tissue) and 4 weeks (2.47 ± 0.02 μmol/g tissue) compared with the control group (3.04 ± 0.15 μmol/g tissue) (Table 2)
Summary
Hepatic mitochondrial dysfunction has been implicated in pathological conditions leading to non-alcoholic steatohepatitis (NASH). ROS directly damages respiratory chain polypeptides and oxidizes the unsaturated lipid of cytoplasmic hepatic fat deposits to cause lipid peroxidation. Both ROS and lipid peroxidation products attack mitochondrial DNA [7]. Oxidative mitochondrial DNA lesions and mitochondrial DNA depletion may impair the synthesis of respiratory chain polypeptides. These effects may further block the flow of electrons in the respiratory chain to further increase mitochondrial ROS formation and decrease the mitochondrial membrane potential [5,8]. Mitochondrial dysfunction is considered to have an important role in the liver during NASH progression since mitochondrial dysfunction causes overproduction of ROS inducing lipid peroxidation, inflammation, and cell death
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