Evaluation of hepatic function using dynamic contrast-enhanced magnetic resonance imaging in melanocortin 4 receptor-deficient mice as a model of nonalcoholic steatohepatitis

Tomomi Yamada, Yuto Kashiwagi, Takemi Rokugawa, Hideaki Kato, Haruyo Konishi, Tadateru Hamada, Ryohei Nagai, Yusaku Masago, Michiko Itoh, Takayoshi Suganami, Yoshihiro Ogawa, Koji Abe

Research output: Contribution to journalArticle

Abstract

Introduction: Melanocortin 4 receptor-deficient (MC4R-KO) mice fed a high-fat diet (HFD) develop liver pathology similar to human nonalcoholic steatohepatitis (NASH). However, although liver histology and blood biochemistry have been reported, hepatic function has not been evaluated. In the present study, we evaluated hepatic function in MC4R-KO mice fed an HFD using dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) with gadolinium‑ethoxybenzyl‑diethylenetriamine pentaacetic acid (Gd-EOB-DTPA). Materials and methods: Wild type (WT) mice and MC4R-KO mice were fed a standard diet (SD) or an HFD for 20 weeks. The hepatic signal intensity was obtained from DCE-MRI images, and relative enhancement (RE), the time to maximum RE (Tmax), and the half-life of RE elimination (T1/2) were calculated. Histopathological analysis was then performed. Results: Histological analysis with nonalcoholic fatty liver disease activity score (NAS) revealed that MC4R-KO mice fed an HFD achieved the NAS of 5. There was moderate fibrosis in MC4R-KO mice fed an HFD. DCE-MRI with Gd-EOB-DTPA showed that Tmax and T1/2 were significantly longer in MC4R-KO mice fed an HFD compared with wild type (WT) mice (Tmax, WT, 3.9 ± 0.4 min; MC4R-KO, 7.4 ± 1.5 min; T1/2, WT, 23.7 ± 1.9 min; MC4R-KO, 62.5 ± 18.5 min). Tmax and T1/2 were significantly correlated with histopathologic score (steatosis vs. Tmax, rho = 0.48, P = 0.04; steatosis vs. T1/2, rho = 0.50, P = 0.03; inflammation vs. Tmax, rho = 0.55, P = 0.02; inflammation vs. T1/2, rho = 0.61, P < 0.01; ballooning vs. T1/2, rho = 0.51, P = 0.03;fibrosis vs Tmax, rho = 0.72, P < 0.01; fibrosis vs T1/2, rho = 0.75, P < 0.01). Conclusions: MC4R-KO mice fed an HFD developed obesity and NASH. The liver kinetics of Gd-EOB-DTPA were significantly different in MC4R-KO mice fed an HFD from WT mice, and correlated with the histopathologic score. These results suggest that MC4R-KO mice fed an HFD mimic the hepatic pathology and liver function of human NASH, and therefore might be useful for the study of hepatic dysfunction during the fibrotic stage of NASH.

Original languageEnglish
Pages (from-to)210-217
Number of pages8
JournalMagnetic Resonance Imaging
Volume57
DOIs
Publication statusPublished - Apr 1 2019
Externally publishedYes

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Magnetic resonance
Nutrition
Oils and fats
High Fat Diet
Magnetic Resonance Imaging
Imaging techniques
Liver
Pathology
Fibrosis
Acids
mouse MC4R protein
Non-alcoholic Fatty Liver Disease
Biochemistry
Histology
Receptor, Melanocortin, Type 4
Image Enhancement
Inflammation
Blood
Half-Life
Obesity

Keywords

  • Dynamic contrast-enhanced-MRI
  • Gd-EOB-DTPA
  • High-fat diet
  • Melanocortin 4 receptor-deficient mice
  • NASH

ASJC Scopus subject areas

  • Biophysics
  • Biomedical Engineering
  • Radiology Nuclear Medicine and imaging

Cite this

Evaluation of hepatic function using dynamic contrast-enhanced magnetic resonance imaging in melanocortin 4 receptor-deficient mice as a model of nonalcoholic steatohepatitis. / Yamada, Tomomi; Kashiwagi, Yuto; Rokugawa, Takemi; Kato, Hideaki; Konishi, Haruyo; Hamada, Tadateru; Nagai, Ryohei; Masago, Yusaku; Itoh, Michiko; Suganami, Takayoshi; Ogawa, Yoshihiro; Abe, Koji.

In: Magnetic Resonance Imaging, Vol. 57, 01.04.2019, p. 210-217.

Research output: Contribution to journalArticle

Yamada, Tomomi ; Kashiwagi, Yuto ; Rokugawa, Takemi ; Kato, Hideaki ; Konishi, Haruyo ; Hamada, Tadateru ; Nagai, Ryohei ; Masago, Yusaku ; Itoh, Michiko ; Suganami, Takayoshi ; Ogawa, Yoshihiro ; Abe, Koji. / Evaluation of hepatic function using dynamic contrast-enhanced magnetic resonance imaging in melanocortin 4 receptor-deficient mice as a model of nonalcoholic steatohepatitis. In: Magnetic Resonance Imaging. 2019 ; Vol. 57. pp. 210-217.
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abstract = "Introduction: Melanocortin 4 receptor-deficient (MC4R-KO) mice fed a high-fat diet (HFD) develop liver pathology similar to human nonalcoholic steatohepatitis (NASH). However, although liver histology and blood biochemistry have been reported, hepatic function has not been evaluated. In the present study, we evaluated hepatic function in MC4R-KO mice fed an HFD using dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) with gadolinium‑ethoxybenzyl‑diethylenetriamine pentaacetic acid (Gd-EOB-DTPA). Materials and methods: Wild type (WT) mice and MC4R-KO mice were fed a standard diet (SD) or an HFD for 20 weeks. The hepatic signal intensity was obtained from DCE-MRI images, and relative enhancement (RE), the time to maximum RE (Tmax), and the half-life of RE elimination (T1/2) were calculated. Histopathological analysis was then performed. Results: Histological analysis with nonalcoholic fatty liver disease activity score (NAS) revealed that MC4R-KO mice fed an HFD achieved the NAS of 5. There was moderate fibrosis in MC4R-KO mice fed an HFD. DCE-MRI with Gd-EOB-DTPA showed that Tmax and T1/2 were significantly longer in MC4R-KO mice fed an HFD compared with wild type (WT) mice (Tmax, WT, 3.9 ± 0.4 min; MC4R-KO, 7.4 ± 1.5 min; T1/2, WT, 23.7 ± 1.9 min; MC4R-KO, 62.5 ± 18.5 min). Tmax and T1/2 were significantly correlated with histopathologic score (steatosis vs. Tmax, rho = 0.48, P = 0.04; steatosis vs. T1/2, rho = 0.50, P = 0.03; inflammation vs. Tmax, rho = 0.55, P = 0.02; inflammation vs. T1/2, rho = 0.61, P < 0.01; ballooning vs. T1/2, rho = 0.51, P = 0.03;fibrosis vs Tmax, rho = 0.72, P < 0.01; fibrosis vs T1/2, rho = 0.75, P < 0.01). Conclusions: MC4R-KO mice fed an HFD developed obesity and NASH. The liver kinetics of Gd-EOB-DTPA were significantly different in MC4R-KO mice fed an HFD from WT mice, and correlated with the histopathologic score. These results suggest that MC4R-KO mice fed an HFD mimic the hepatic pathology and liver function of human NASH, and therefore might be useful for the study of hepatic dysfunction during the fibrotic stage of NASH.",
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TY - JOUR

T1 - Evaluation of hepatic function using dynamic contrast-enhanced magnetic resonance imaging in melanocortin 4 receptor-deficient mice as a model of nonalcoholic steatohepatitis

AU - Yamada, Tomomi

AU - Kashiwagi, Yuto

AU - Rokugawa, Takemi

AU - Kato, Hideaki

AU - Konishi, Haruyo

AU - Hamada, Tadateru

AU - Nagai, Ryohei

AU - Masago, Yusaku

AU - Itoh, Michiko

AU - Suganami, Takayoshi

AU - Ogawa, Yoshihiro

AU - Abe, Koji

PY - 2019/4/1

Y1 - 2019/4/1

N2 - Introduction: Melanocortin 4 receptor-deficient (MC4R-KO) mice fed a high-fat diet (HFD) develop liver pathology similar to human nonalcoholic steatohepatitis (NASH). However, although liver histology and blood biochemistry have been reported, hepatic function has not been evaluated. In the present study, we evaluated hepatic function in MC4R-KO mice fed an HFD using dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) with gadolinium‑ethoxybenzyl‑diethylenetriamine pentaacetic acid (Gd-EOB-DTPA). Materials and methods: Wild type (WT) mice and MC4R-KO mice were fed a standard diet (SD) or an HFD for 20 weeks. The hepatic signal intensity was obtained from DCE-MRI images, and relative enhancement (RE), the time to maximum RE (Tmax), and the half-life of RE elimination (T1/2) were calculated. Histopathological analysis was then performed. Results: Histological analysis with nonalcoholic fatty liver disease activity score (NAS) revealed that MC4R-KO mice fed an HFD achieved the NAS of 5. There was moderate fibrosis in MC4R-KO mice fed an HFD. DCE-MRI with Gd-EOB-DTPA showed that Tmax and T1/2 were significantly longer in MC4R-KO mice fed an HFD compared with wild type (WT) mice (Tmax, WT, 3.9 ± 0.4 min; MC4R-KO, 7.4 ± 1.5 min; T1/2, WT, 23.7 ± 1.9 min; MC4R-KO, 62.5 ± 18.5 min). Tmax and T1/2 were significantly correlated with histopathologic score (steatosis vs. Tmax, rho = 0.48, P = 0.04; steatosis vs. T1/2, rho = 0.50, P = 0.03; inflammation vs. Tmax, rho = 0.55, P = 0.02; inflammation vs. T1/2, rho = 0.61, P < 0.01; ballooning vs. T1/2, rho = 0.51, P = 0.03;fibrosis vs Tmax, rho = 0.72, P < 0.01; fibrosis vs T1/2, rho = 0.75, P < 0.01). Conclusions: MC4R-KO mice fed an HFD developed obesity and NASH. The liver kinetics of Gd-EOB-DTPA were significantly different in MC4R-KO mice fed an HFD from WT mice, and correlated with the histopathologic score. These results suggest that MC4R-KO mice fed an HFD mimic the hepatic pathology and liver function of human NASH, and therefore might be useful for the study of hepatic dysfunction during the fibrotic stage of NASH.

AB - Introduction: Melanocortin 4 receptor-deficient (MC4R-KO) mice fed a high-fat diet (HFD) develop liver pathology similar to human nonalcoholic steatohepatitis (NASH). However, although liver histology and blood biochemistry have been reported, hepatic function has not been evaluated. In the present study, we evaluated hepatic function in MC4R-KO mice fed an HFD using dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) with gadolinium‑ethoxybenzyl‑diethylenetriamine pentaacetic acid (Gd-EOB-DTPA). Materials and methods: Wild type (WT) mice and MC4R-KO mice were fed a standard diet (SD) or an HFD for 20 weeks. The hepatic signal intensity was obtained from DCE-MRI images, and relative enhancement (RE), the time to maximum RE (Tmax), and the half-life of RE elimination (T1/2) were calculated. Histopathological analysis was then performed. Results: Histological analysis with nonalcoholic fatty liver disease activity score (NAS) revealed that MC4R-KO mice fed an HFD achieved the NAS of 5. There was moderate fibrosis in MC4R-KO mice fed an HFD. DCE-MRI with Gd-EOB-DTPA showed that Tmax and T1/2 were significantly longer in MC4R-KO mice fed an HFD compared with wild type (WT) mice (Tmax, WT, 3.9 ± 0.4 min; MC4R-KO, 7.4 ± 1.5 min; T1/2, WT, 23.7 ± 1.9 min; MC4R-KO, 62.5 ± 18.5 min). Tmax and T1/2 were significantly correlated with histopathologic score (steatosis vs. Tmax, rho = 0.48, P = 0.04; steatosis vs. T1/2, rho = 0.50, P = 0.03; inflammation vs. Tmax, rho = 0.55, P = 0.02; inflammation vs. T1/2, rho = 0.61, P < 0.01; ballooning vs. T1/2, rho = 0.51, P = 0.03;fibrosis vs Tmax, rho = 0.72, P < 0.01; fibrosis vs T1/2, rho = 0.75, P < 0.01). Conclusions: MC4R-KO mice fed an HFD developed obesity and NASH. The liver kinetics of Gd-EOB-DTPA were significantly different in MC4R-KO mice fed an HFD from WT mice, and correlated with the histopathologic score. These results suggest that MC4R-KO mice fed an HFD mimic the hepatic pathology and liver function of human NASH, and therefore might be useful for the study of hepatic dysfunction during the fibrotic stage of NASH.

KW - Dynamic contrast-enhanced-MRI

KW - Gd-EOB-DTPA

KW - High-fat diet

KW - Melanocortin 4 receptor-deficient mice

KW - NASH

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