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

Takemi Rokugawa, Haruyo Konishi, Miwa Ito, Hitoshi Iimori, Ryohei Nagai, Eku Shimosegawa, Jun Hatazawa, Koji Abe

Research output: Contribution to journalArticle

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Abstract

Background: Activated 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. 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. 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. Conclusions: The 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.

Original languageEnglish
Article number40
JournalEJNMMI Research
Volume8
Issue number1
DOIs
Publication statusPublished - Dec 1 2018
Externally publishedYes

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High Fat Diet
Fatty Liver
Choline
Integrins
Amino Acids
Liver
Fibrosis
Pathology
Inflammation
FB-NH-PEG4-E(PEG4-c(RGDfK))2
Hepatic Stellate Cells
Rubiaceae
Collagen Type I
Inbred C57BL Mouse
Biochemistry
Smooth Muscle
Actins
Proteins
Messenger RNA

Keywords

  • F-FPP-RGD
  • Fibrosis
  • High-fat diet
  • Integrin αvβ3
  • Modified methionine choline-deficient
  • Non-alcoholic fatty liver disease
  • Non-alcoholic steatohepatitis
  • Positron emission tomography

ASJC Scopus subject areas

  • Radiology Nuclear Medicine and imaging

Cite this

Evaluation of hepatic integrin αvβ3 expression in non-alcoholic steatohepatitis (NASH) model mouse by 18F-FPP-RGD2 PET. / Rokugawa, Takemi; Konishi, Haruyo; Ito, Miwa; Iimori, Hitoshi; Nagai, Ryohei; Shimosegawa, Eku; Hatazawa, Jun; Abe, Koji.

In: EJNMMI Research, Vol. 8, No. 1, 40, 01.12.2018.

Research output: Contribution to journalArticle

Rokugawa, Takemi ; Konishi, Haruyo ; Ito, Miwa ; Iimori, Hitoshi ; Nagai, Ryohei ; Shimosegawa, Eku ; Hatazawa, Jun ; Abe, Koji. / Evaluation of hepatic integrin αvβ3 expression in non-alcoholic steatohepatitis (NASH) model mouse by 18F-FPP-RGD2 PET. In: EJNMMI Research. 2018 ; Vol. 8, No. 1.
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abstract = "Background: Activated 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. 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. 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. Conclusions: The 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.",
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year = "2018",
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language = "English",
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T1 - Evaluation of hepatic integrin αvβ3 expression in non-alcoholic steatohepatitis (NASH) model mouse by 18F-FPP-RGD2 PET

AU - Rokugawa, Takemi

AU - Konishi, Haruyo

AU - Ito, Miwa

AU - Iimori, Hitoshi

AU - Nagai, Ryohei

AU - Shimosegawa, Eku

AU - Hatazawa, Jun

AU - Abe, Koji

PY - 2018/12/1

Y1 - 2018/12/1

N2 - Background: Activated 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. 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. 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. Conclusions: The 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.

AB - Background: Activated 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. 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. 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. Conclusions: The 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.

KW - F-FPP-RGD

KW - Fibrosis

KW - High-fat diet

KW - Integrin αvβ3

KW - Modified methionine choline-deficient

KW - Non-alcoholic fatty liver disease

KW - Non-alcoholic steatohepatitis

KW - Positron emission tomography

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U2 - 10.1186/s13550-018-0394-4

DO - 10.1186/s13550-018-0394-4

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