Abstract
BackgroundActivated hepatic stellate cells (HSCs), which express integrin αvβ3, are a major fibrogenic factor in NASH pathophysiology. 18F-labeled cyclic arginine-glycine-aspartic acid penta-peptide (18F-FPP-RGD2) 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 18F-FPP-RGD2 to detect hepatic integrin αvβ3 expression in non-alcoholic steatohepatitis (NASH) model mice.ResultsThirty-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. 18F-FPP-RGD2 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, SUV80–90 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 18F-FPP-RGD2 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 18F-FPP-RGD2 uptake also showed a positive correlation with Sirius red-positive area.ConclusionsThe hepatic uptake of 18F-FPP-RGD2 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.
Highlights
Activated hepatic stellate cells (HSCs), which express integrin αvβ3, are a major fibrogenic factor in non-alcoholic steatohepatitis (NASH) pathophysiology. 18F-labeled cyclic arginine-glycine-aspartic acid penta-peptide (18F-FPP-RGD2) has been used as a positron emission tomography (PET) probe for tumors expressing integrin αvβ3
We investigated the relationship between the hepatic uptake of 18F-FPP-RGD2 and integrin αvβ3 expression using PET imaging in a NASH mouse model induced by feeding with a choline-deficient, L-amino acid-defined, high-fat diet (CDAHFD) [22]
Higher uptake of 18F-FPP-RGD2 was observed in mice fed the CDAHFD for 3 and 8 weeks compared with control mice
Summary
Activated hepatic stellate cells (HSCs), which express integrin αvβ, are a major fibrogenic factor in NASH pathophysiology. 18F-labeled cyclic arginine-glycine-aspartic acid penta-peptide (18F-FPP-RGD2) has been used as a PET probe for tumors expressing integrin αvβ. The aim of this study was to assess the potential of PET with 18F-FPP-RGD2 to detect hepatic integrin αvβ expression in non-alcoholic steatohepatitis (NASH) model mice. Magnetic resonance elastography and ultrasound-based transient elastography have been developed to assess liver fibrosis [6, 7]. These methods can discriminate moderate and advanced liver fibrosis from early-stage liver injury or the normal patient population. Especially in NASH patients, steatosis may produce a softer liver because of fat deposition in the liver parenchyma [9, 10] These non-invasive tools are not likely to be sensitive enough to identify mild changes or early stages of fibrosis. The development of sensitive imaging markers of fibrogenesis is important to predict the prognosis and determine the precise therapeutic intervention required
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