Theranostics 2017; 7(17):4192-4203. doi:10.7150/thno.21400 This issue Cite

Research Paper

Pro-Inflammatory CXCR3 Impairs Mitochondrial Function in Experimental Non-Alcoholic Steatohepatitis

Jinghua Du1, 2*, Xiang Zhang1*, Juqiang Han1, 3, Kwan Man4, Yanquan Zhang1, Eagle SH Chu1, Yuemin Nan2✉, Jun Yu1✉

1. Institute of Digestive Disease and The Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, CUHK-Shenzhen Research Institute, The Chinese University of Hong Kong, Hong Kong
2. Department of Traditional and Western Medical Hepatology, Third Hospital of Hebei Medical University, Shijiazhuang, China
3. Institute of liver disease, Beijing Military General Hospital, Beijing, China
4. Department of Surgery, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong
* These authors contributed equally to this work.

Citation:
Du J, Zhang X, Han J, Man K, Zhang Y, Chu ESH, Nan Y, Yu J. Pro-Inflammatory CXCR3 Impairs Mitochondrial Function in Experimental Non-Alcoholic Steatohepatitis. Theranostics 2017; 7(17):4192-4203. doi:10.7150/thno.21400. https://www.thno.org/v07p4192.htm
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Abstract

Graphic abstract

Mitochondrial dysfunction plays a crucial role in the development of non-alcoholic steatohepatitis (NASH). However, the regulator of mitochondrial dysfunction in the pathogenesis of NASH is still largely unclear. CXCR3 is an essential pro-inflammatory factor in chronic liver diseases. We explored the significance of CXCR3 in regulating mitochondrial function during NASH development in animal models and cultured hepatocytes.

Methods: The effects of CXCR3 on mitochondrial function were evaluated by genetic knockout or pharmacological inhibition in mouse models and in vitro. The ultrastructural changes of mitochondria were assessed by transmission electron microscopy (TEM). Hepatic levels of mitochondrial reactive oxygen species (ROS), DNA damage, membrane potential and ATP were examined.

Results: CXCR3 ablation by genetic knockout or pharmacological inhibition in mice protected against NASH development by influencing mitochondrial function. Similarly, depletion of CXCR3 reduced steatohepatitis injury in cultured hepatocytes. TEM analysis revealed that liver mitochondrial integrity was much improved in CXCR3 knockout (CXCR3-/-) compared to wildtype (WT) mice. In agreement with this, impaired mitochondrial function was pronounced in WT mice compared to CXCR3-/- mice, evidenced by increased protein expression of dynamic-related protein-1 (DRP1) and fission-1 (FIS1) and decreased protein expression of mitofusin-1 (MFN1). Mitochondrial dysfunction was induced in AML-12 hepatocytes by methionine and choline deficient medium and in HepG2 cells by palmitic acid. The impaired mitochondrial function in both cell lines was evidenced by reduced membrane potential and ATP content, and by increased mitochondrial ROS accumulation and DNA damage. However, CXCR3 knockdown by siCXCR3 significantly diminished the mitochondrial dysfunction in both AML-12 and HepG2 hepatocytes. In addition, inhibition of CXCR3 by CXCR3 specific antagonists SCH546738 and AMG487 restored mitochondrial function and inhibited mitochondrial-dependent apoptosis in the liver of WT mice fed with methionine and choline deficient diet.

Conclusion: CXCR3 induces mitochondrial dysfunction, which contributes to the pathogenesis of steatohepatitis. Pharmacologic blockade of CXCR3 prevents mitochondrial dysfunction and restores the severity of steatohepatitis, indicating a potential clinical impact for controlling the disease.

Keywords: CXCR3, non-alcoholic fatty liver diseases, mitochondria, apoptosis.


Citation styles

APA
Du, J., Zhang, X., Han, J., Man, K., Zhang, Y., Chu, E.SH., Nan, Y., Yu, J. (2017). Pro-Inflammatory CXCR3 Impairs Mitochondrial Function in Experimental Non-Alcoholic Steatohepatitis. Theranostics, 7(17), 4192-4203. https://doi.org/10.7150/thno.21400.

ACS
Du, J.; Zhang, X.; Han, J.; Man, K.; Zhang, Y.; Chu, E.SH.; Nan, Y.; Yu, J. Pro-Inflammatory CXCR3 Impairs Mitochondrial Function in Experimental Non-Alcoholic Steatohepatitis. Theranostics 2017, 7 (17), 4192-4203. DOI: 10.7150/thno.21400.

NLM
Du J, Zhang X, Han J, Man K, Zhang Y, Chu ESH, Nan Y, Yu J. Pro-Inflammatory CXCR3 Impairs Mitochondrial Function in Experimental Non-Alcoholic Steatohepatitis. Theranostics 2017; 7(17):4192-4203. doi:10.7150/thno.21400. https://www.thno.org/v07p4192.htm

CSE
Du J, Zhang X, Han J, Man K, Zhang Y, Chu ESH, Nan Y, Yu J. 2017. Pro-Inflammatory CXCR3 Impairs Mitochondrial Function in Experimental Non-Alcoholic Steatohepatitis. Theranostics. 7(17):4192-4203.

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