Abstract
BackgroundNonalcoholic fatty liver disease is a common disorder that progresses from simple fatty liver (steatosis) to nonalcoholic steatohepatitis (NASH). It is thought that mitochondrial dysfunction plays a critical role in the progression of NASH. In this study, we developed a non-invasive method for early diagnosis and staging of NASH that directly measures mitochondrial complex-I (MC-I) activity in the liver of NASH model mice by positron emission tomography (PET) imaging using the novel tracer 2-tert-butyl-4-chloro-5-[6-(4-[18F]fluorobutoxy)-pyridin-3-ylmethoxy]-2H-pyridazin-3-one (18F-BCPP-BF). Liver uptake of 18F-BCPP-BF in NASH and age-matched control mice was measured as a standard uptake value over a period of 1 to 12 weeks. Histopathological evaluation of the liver tissue was performed by haematoxylin and eosin staining, and fibrosis was assessed by Masson’s trichrome staining.ResultsSignificant mitochondrial dysfunction was detected as early as 1 week after commencing the diet, and MC-I activity in the liver measured by PET was reduced by > 50% relative to that in age-matched control mice after 6 weeks. Liver uptake of 18F-BCPP-BF was low throughout the 12-week experimental period. Histopathological examination revealed that steatosis, inflammation, and ballooning progressed from 1 to 6 weeks, with fibrosis observed from 6 to 12 weeks.ConclusionsPET scans and histopathological analysis revealed that mitochondrial dysfunction in the liver contributed to the progression of NASH. PET imaging with 18F-BCPP-BF is a useful tool for detecting NASH at early stages and for monitoring therapeutic response.
Highlights
Nonalcoholic fatty liver disease is a common disorder that progresses from simple fatty liver to nonalcoholic steatohepatitis (NASH)
Liver uptake of 18F-BCPP-BF was significantly reduced after just 1 week and continued to decline up to 6 weeks, at which point it remained at a very low level
In contrast to the pattern in control group, time-activity curve (TAC) in the liver of NASH mice were almost independent of the duration of exposure to CDAHFD
Summary
Nonalcoholic fatty liver disease is a common disorder that progresses from simple fatty liver (steatosis) to nonalcoholic steatohepatitis (NASH). We developed a non-invasive method for early diagnosis and staging of NASH that directly measures mitochondrial complex-I (MC-I) activity in the liver of NASH model mice by positron emission tomography (PET) imaging using the novel tracer 2-tert-butyl-4-chloro-5-[6-(4-[18F]fluorobutoxy)-pyridin-3-ylmethoxy]-2H-pyridazin-3-one (18F-BCPP-BF). We recently succeeded in imaging hepatic mitochondrial dysfunction induced by acetaminophen using 2-tert-butyl-4-chloro-5-[6-(4-[18F]fluorobutoxy)-pyridin-3-ylmethoxy]-2H-pyridazin-3-one (18F-BCPP-BF) as tracer. Pre-administration of rotenone (0.1 mg/kg/h), a specific MC-I inhibitor, markedly decreased liver uptake of 18F-BCPP-BF, indicating that liver uptake of this probe was mainly due to specific binding to MC-I. These results suggest that this method can be used to measure mitochondrial dysfunction during NAFLD progression with high sensitivity
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