FAM3A mediates PPARγ's protection in liver ischemia-reperfusion injury by activating Akt survival pathway and repressing inflammation and oxidative stress
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Zhenzhen Chen1,2,*, Junpei Wang2,*, Weili Yang1, Ji Chen1, Yuhong Meng1, Bin Geng3, Qinghua Cui2 and Jichun Yang1
1Department of Physiology and Pathophysiology, School of Basic Medical Sciences Key Laboratory of Molecular Cardiovascular Sciences of the Ministry of Education Center for Non-coding RNA Medicine, Peking University Health Science Center, Beijing 100191, China
2Department of Biomedical Informatics, School of Basic Medical Sciences Key Laboratory of Molecular Cardiovascular Sciences of the Ministry of Education, Center for Non-coding RNA Medicine, Peking University Health Science Center, Beijing 100191, China
3State Key Laboratory of Cardiovascular Disease, Fuwai Hospital of Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing 100037, China
*These authors have contributed equally to this work
Jichun Yang, email: firstname.lastname@example.org
Qinghua Cui, email: email@example.com
Keywords: liver ischemia/reperfusion injury, FAM3A, PPARgamma, Akt, FOXO1
Received: June 03, 2016 Accepted: April 12, 2017 Published: May 11, 2017
FAM3A is a novel mitochondrial protein, and its biological function remains largely unknown. This study determined the role and mechanism of FAM3A in liver ischemia-reperfusion injury (IRI). In mouse liver after IRI, FAM3A expression was increased. FAM3A-deficient mice exhibited exaggerated liver damage with increased serum levels of AST, ALT, MPO, MDA and oxidative stress when compared with WT mice after liver IRI. FAM3A-deficient mouse livers had a decrease in ATP content, Akt activity and anti-apoptotic protein expression with an increase in apoptotic protein expression, inflammation and oxidative stress when compared WT mouse livers after IRI. Rosiglitazone pretreatment protected against liver IRI in wild type mice but not in FAM3A-deficient mice. In cultured hepatocytes, FAM3A overexpression protected against, whereas FAM3A deficiency exaggerated oxidative stress-induced cell death. FAM3A upregulation or FAM3A overexpression inhibited hypoxia/reoxygenation-induced activation of apoptotic gene and hepatocyte death in P2 receptor-dependent manner. FAM3A deficiency blunted rosiglitazone’s beneficial effects on Akt activation and cell survival in cultured hepatocytes. Collectively, FAM3A protects against liver IRI by activating Akt survival pathways, repressing inflammation and attenuating oxidative stress. Moreover, the protective effects of PPARγ agonist(s) on liver IRI are dependent on FAM3A-ATP-Akt pathway.
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