Resistin reduces mitochondria and induces hepatic steatosis in mice by the protein kinase C/protein kinase G/p65/PPAR gamma coactivator 1 alpha pathway

被引:50
作者
Zhou, Lei [1 ]
Yu, Xiaolan [1 ]
Meng, Qingjie [1 ]
Li, Hongqiang [1 ]
Niu, Congcong [1 ]
Jiang, Yun [1 ]
Cai, Yuxi [1 ]
Li, Minghui [1 ]
Li, Qiang [1 ]
An, Chaoqiang [1 ]
Shu, Le [1 ]
Chen, Ao [1 ]
Su, Handong [1 ]
Tang, Yin [1 ]
Yin, Shen [1 ]
Raschke, Silja [2 ]
Eckardt, Kristin [2 ]
Eckel, Juergen [2 ]
Yang, Zaiqing [1 ]
机构
[1] Huazhong Agr Univ, Coll Life Sci & Technol, Key Lab Agr Anim Genet Breeding & Reprod, Minist Educ, Wuhan 430070, Hubei Province, Peoples R China
[2] German Diabet Ctr, Paul Langerhans Grp Integrat Physiol, Dusseldorf, Germany
基金
中国国家自然科学基金;
关键词
FATTY LIVER-DISEASE; NF-KAPPA-B; INSULIN-RESISTANCE; DNA DAMAGE; CYCLIC-GMP; OBESITY; PHOSPHORYLATION; DYSFUNCTION; CELLS; ADIPONECTIN;
D O I
10.1002/hep.26167
中图分类号
R57 [消化系及腹部疾病];
学科分类号
摘要
Obesity is associated with many severe chronic diseases and deciphering its development and molecular mechanisms is necessary for promoting treatment. Previous studies have revealed that mitochondrial content is down-regulated in obesity, diabetes, and nonalcoholic fatty liver disease (NAFLD) and proposed that NAFLD and diabetes are mitochondrial diseases. However, the exact mechanisms underlying these processes remain unclear. In this study, we discovered that resistin down-regulated the content and activities of mitochondria, enhanced hepatic steatosis, and induced insulin resistance (IR) in mice. The time course indicated that the change in mitochondrial content was before the change in fat accumulation and development of insulin resistance. When the mitochondrial content was maintained, resistin did not stimulate hepatic fat accumulation. The present mutation study found that the residue Thr464 of the p65 subunit of nuclear factor kappa B was essential for regulating mitochondria. A proximity ligation assay revealed that resistin inactivated peroxisome proliferator activated receptor gamma coactivator 1 alpha (PGC-1) and diminished the mitochondrial content by promoting the interaction of p65 and PGC-1. Signaling-transduction analysis demonstrated that resistin down-regulated mitochondria by a novel protein kinase C/protein kinase G/p65/PGC-1-signaling pathway. Conclusion: Resistin induces hepatic steatosis through diminishing mitochondrial content. This reveals a novel pathway for mitochondrial regulation, and suggests that the maintenance of normal mitochondrial content could be a new strategy for treatment of obesity-associated diseases. (HEPATOLOGY 2013)
引用
收藏
页码:1384 / 1393
页数:10
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