In vivo redox metabolic imaging of mitochondria assesses disease progression in non-alcoholic steatohepatitis

Ryosuke Nakata,Hinako Eto,Sayoko Narahara,Takahito Kawano,Masaharu Murata,Tomoko Nakaji,Makoto Hashizume,Keiji Yasukawa,Morimasa Tomikawa,Tomohiko Akahoshi,Fuminori Hyodo

doi:10.1038/s41598-017-17447-2

Abstract

Given the rising incidence of non-alcoholic fatty liver disease (NAFLD) in both adults and children, the development of a non-invasive diagnostic method for assessing disease progression to non-alcoholic steatohepatitis (NASH) has become an important research goal. Currently available non-invasive imaging technologies are only able to assess fat accumulation in the liver. Therefore, these methods are not suitable for a precise diagnosis of NASH. The standard diagnostic technique for NASH, liver biopsy, has several drawbacks, including the higher risk of complications that accompanies invasive procedures. Here, we demonstrated that in vivo mitochondrial redox metabolism was dramatically altered at an early stage, before histopathological changes, and NASH could be accurately diagnosed by in vivo dynamic nuclear polarization-magnetic resonance imaging, with carbamoyl-PROXYL as a molecular imaging probe. In addition, this technique was feasible for the diagnosis of NASH compared with histopathological findings from biopsies. Our data reveal a novel method for monitoring the dynamics of redox metabolic changes in NAFLD/NASH.

Highlights

As a consequence of the global epidemic of metabolic syndrome and chronic obesity, non-alcoholic fatty liver disease (NAFLD) has emerged as an important contribution in several chronic liver diseases[1,2,3]
A non-invasive diagnostic strategy is strongly desirable for the paediatric population because liver biopsy is associated with pain and a higher risk of complications than in adult patients. This is the first study to directly investigate the liver redox status related mitochondrial function of a non-alcoholic steatohepatitis (NASH) mouse model using non-invasive, in vivo dynamic nuclear polarization-magnetic resonance imaging (DNP-MRI) and CmP as radical probe unlike the previous reports aiming for clinical application of DNP-MRI
A direct reaction between liver homogenates and CmP strongly supported the results of in vivo DNP-MRI, and the dynamics of CmP reduction changes corresponded to disease progression, with excess oxidative stress detected earlier than by immunohistochemical analysis of 8-OHdG and 4-HNE

Summary

Introduction

As a consequence of the global epidemic of metabolic syndrome and chronic obesity, non-alcoholic fatty liver disease (NAFLD) has emerged as an important contribution in several chronic liver diseases[1,2,3]. Ultrastructural abnormalities and mitochondrial dysfunction are observed in the liver of animal models and patients with NASH14,15 Based on these findings, the redox status in NASH, in the context of mitochondria as the main source of ROS, has been investigated[16,17,18]. Previous studies revealed that these compounds protected mammalian cells against oxidative damages, despite having no direct catalase activity[23,24,25] These results suggested that nitroxyl compounds intercept intracellular oxygen radicals and could exert antioxidant effects. We evaluated the feasibility of in vivo mitochondrial redox status, assessed by DNP-MRI with CmP as a molecular imaging probe, for determining the disease stage in NASH, and to distinguish between NAFLD and NASH

Methods

Results

Conclusion