In the present study,
18F-BMS was used to evaluate hepatic MC-1 activity in mice fed MCD diet as a model of NAFLD.
18F-BMS has been investigated as a PET myocardial perfusion imaging agent for both clinical and non-clinical use [
19,
20].
18F-BMS was reported to bind tightly to cellular MC-1, which is the first component of the four electron transport complexes in the inner mitochondrial membrane [
16].
18F-BMS is selectively taken up into the heart because of the high density of mitochondria in the cardiac muscle. There are some reports that uptake of MC-1 probes, including
18F-BMS, was inhibited by pre-injection of rotenone, a MC-1 inhibitor not only in the heart but also in the brain [
21,
22]. In the present study, hepatic uptake of
18F-BMS was also reduced by pre-injection of rotenone, indicating that
18F-BMS is bound to MC-1 in the liver. Furthermore, the most interesting finding of the present study was that hepatic MC-1 activity was correlated with hepatic
18F-BMS uptake. Thus, these results indicate that hepatic uptake of
18F-BMS also depends on MC-1 activity. In the present study, a MC-1 immunocaptured dipstick assay kit, which measured MC-1-specific NADH oxidase activity was used. This method has been used in several tissues, including mouse liver, and was previously used to detect a tetracycline-induced decrease in hepatic MC-1 activity [
23]. Notably, MC-1 activity was also significantly decreased at 2 weeks in mice fed a MCD diet. In a rat study, 11 weeks of a MCD diet decreased MC-1 activity over 70% [
24]. It was also reported that a prolonged MCD diet progressed NAFLD pathology [
24,
25]. In our previous study, NAFLD severity increased with duration of MCD diet [
25]. Although after 2 weeks of the MCD diet no fibrosis was observed, 4 weeks of a MCD diet induced weak fibrosis and liver fibrosis was clearly observed at 6 weeks [
25]. In the present study, 1 and 2 weeks of a MCD diet revealed weak or mild steatosis and weak inflammation in mice. Therefore, up to 2 weeks of a MCD diet represents a model for early-stage NAFLD. Multiple studies support the observation that mitochondrial dysfunction is involved in the development of NASH [
8,
26,
27]. Mitochondria generate ROS which damage the mitochondrial respiratory complex, decrease mitochondrial membrane potential, and cause ATP depletion [
27]. In the setting of NAFLD, there are reports regarding mitochondrial respiratory chain enzymes in NASH patients. Perez et al. reported a lower activity of the five mitochondrial respiratory complexes in patients with NASH [
28]. Thus, our study indicated that
18F-BMS might be useful as a high-resolution imaging method for the diagnosis of patients with NAFLD.
In an in vivo microscopic study, blood perfusion of the liver of mice fed MCD diet for 3 and 5 weeks was decreased by 13 and 19% respectively [
29]. There was no study to evaluate blood perfusion of the liver of mice fed a MCD diet for 1 or 2 weeks. In our previous dynamic enhanced MRI study,
T
max and
T
1/2 after injection of gadolinium-ethoxybenzyl-diethylenetriamine penta-acetic acid (Gd-EOB-DTPA) were not changed at MCD diet for 2 weeks fed mice and were prolonged at MCD diet for 6 weeks fed mice [
25]. Therefore, in the evaluation of
18F-BMS uptake, there may be little influence of hepatic blood flow. Further study will be needed to clarify the effect of blood flow on
18F-BMS uptake in the liver of MCD mice. Thus, the decrease of
18F-BMS hepatic uptake might be due to the decrease of MC-1 activity rather than the hepatic perfusion in mice fed a MCD diet for 2 weeks. In our previous study, hepatic clearance of
99mTc-MIBI was changed in mice fed with MCD diet for 2 weeks. These changes have indicated that hepatic mitochondrial membrane potential was decreased at 2 weeks after MCD diet. Thus, non-invasive mitochondrial function imaging such as
18F-BMS and
99mTc-MIBI might be useful for NAFLD evaluation.