Mark4 promotes oxidative stress and inflammation via binding to PPARγ and activating NF-κB pathway in mice adipocytes.

Zhenjiang Liu,Xueting Lin,Zhenzhen Zhang,Zhongjie Zhou,Lu Gan,Chao Sun,Dan Luo,Yizhe Chen,Weina Cao

doi:10.1038/srep21382

Zhenjiang Liu, Xueting Lin + Show 7 more

Open Access

https://doi.org/10.1038/srep21382

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Abstract

MAP/Microtubule affinity-regulating kinase 4 (Mark4) plays an important role in the regulation of microtubule organization, adipogenesis and apoptosis. However, the role of Mark4 plays in oxidative stress and inflammation are poorly understood. In this study, we found Mark4 was induced by high fat diet (HFD) while PPARγ was elevated significantly in mice adipocytes. Further analyses revealed Mark4 impaired mitochondrial oxidative respiration and increased reactive oxygen species (ROS) production. At same time, the activities of superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx) were greatly reduced. By treating cells with H2O2 and vitamin E (VE), Mark4 accentuated oxidative stress along with increased mRNA level of inflammatory factor interleukin-6 (IL-6) and decreased leptin mRNA. Furthermore, we found PPARγ bind to Mark4 promoter region and inhibited Mark4 expression. We showed PPARγ interacted with Mark4 and inhibited the stimulating effect of Mark4 on oxidative stress and inflammation. Finally, we demonstrated that the IKKα/NF-κB signal pathway was involved in Mark4 induced oxidative stress and inflammation, while PTDC, a special inhibitor of NF-κB signal pathway, reduced oxidative stress and inflammation. Thus, our study indicated that Mark4 was a potential drug target for treating metabolic diseases.

Highlights

Microtubules affinity regulated kinase 4 (Mark4), one of the microtubule affinity-regulating kinases (MARKs) family member, is expressed in multiple tissues[1]
Since high fat diet (HFD) disrupted body metabolism, we examined the effect of HFD on oxidative stress and adipose inflammation, which showed HFD increased the activities of superoxide dismutase (SOD), MDA and reactive oxygen species (ROS) (Fig. 1E)
We addressed whether Mark[4] was involved in oxidative stress production

Summary

Introduction

Microtubules affinity regulated kinase 4 (Mark4), one of the microtubule affinity-regulating kinases (MARKs) family member, is expressed in multiple tissues[1]. Feng et al (2014) further determines that Mark[4] promotes adipogenesis and triggers adipocytes apoptosis[7] These data establish that Mark[4] increases body glucose homeostasis and energy metabolism. Our pervious data indicate that Mark[4] promotes adipocytes apoptosis, we hypothesize that Mark[4] increases adipose oxidative stress. We found PPARγ and Mark[4] interacted directly to inhibit adipose oxidative stress and inflammation. These findings illustrate a novel function of Mark[4] in the regulation of cell oxidative stress and energy balance, and Mark[4] may serve as a potential drug target for treating metabolic syndrome

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