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Background  Activated hepatic stellate cells (HSCs), which express integrin αvβ3, are a major fibrogenic factor in NASH pathophysiology.  18 F-labeled cyclic arginine-glycine-aspartic acid penta-peptide ( 18 F-FPP-RGD 2 ) has been used as a PET probe for tumors expressing integrin αvβ3. The aim of this study was to assess the potential of PET with  18 F-FPP-RGD 2  to detect hepatic integrin αvβ3 expression in non-alcoholic steatohepatitis (NASH) model mice.    Results  Thirty-two male C57BL/6 mice aged 6 weeks were fed a choline-deficient,  l -amino acid-defined, high-fat diet (CDAHFD) for 3 and 8 weeks.  18 F-FPP-RGD 2  PET imaging of the liver was performed at 3 and 8 weeks after CDAHFD feeding. After PET scanning, levels of hepatic integrin αvβ, 3α-smooth muscle actin (α-SMA), and collagen type 1 alpha 1(col1a1) were measured. Histopathological analysis of hepatic steatosis, inflammation, and fibrosis, as well as blood biochemistry analysis, was also performed. CDAHFD for 3 and 8 weeks produced a moderate-to-severe steatosis and inflammation of the liver in mice. NAFLD activity score (NAS) in mice fed the CDAHFD for 3 and 8 weeks were more than 4 indicating NASH or borderline NASH pathology. Fibrosis was observed only in mice fed the CDAHFD for 8 weeks. PET imaging showed that the hepatic standardized uptake value, SUV 80–90 min , was increased with prolonged CDAHFD feeding compared with the respective controls (CDAHFD 3 weeks 0.32 ± 0.06 vs 0.48 ± 0.05,  p  < 0.01; CDAHFD 8 weeks 0.35 ± 0.04 vs 0.75 ± 0.07,  p  < 0.01, respectively). Prolonged CDAHFD feeding increased hepatic mRNA and protein levels of integrin αv and β3 at 3 and 8 weeks. Hepatic  18 F-FPP-RGD 2  uptake and amount of integrin αv and β3 protein were well correlated ( r  = 0.593,  p  < 0.05 and  r  = 0.835,  p  < 0.001, respectively). Hepatic  18 F-FPP-RGD 2  uptake also showed a positive correlation with Sirius red-positive area.    Conclusions  The hepatic uptake of  18 F-FPP-RGD 2  correlated well with integrin αv and β3 expression and histological fibrosis in a mouse model of NASH, suggesting the predictability of fibrosis in NASH pathology.

Evaluation of hepatic integrin αvβ3 expression in non-alcoholic steatohepatitis (NASH) model mouse by 18F-FPP-RGD2 PET