Lu Yan, Liu Xing, Jiao Yang, Xiong Xuelian, Wang E, Wang Xiaolin, Zhang Zhijian, Zhang Huijie, Pan Lingling, Guan Youfei, Cai Dongsheng, Ning Guang, Li Xiaoying
J Clin Invest. 2014 Aug;124(8):3501-13. doi: 10.1172/JCI74438. Epub 2014 Jul 8.
Hepatosteatosis is characterized by an aberrant accumulation of triglycerides in the liver; however, the factors that drive obesity-induced fatty liver remain largely unknown. Here, we demonstrated that the secreted cell adhesion protein periostin is markedly upregulated in livers of obese rodents and humans. Notably, overexpression of periostin in the livers of WT mice promoted hepatic steatosis and hypertriglyceridemia. Conversely, both genetic ablation of periostin and administration of a periostin-neutralizing antibody dramatically improved hepatosteatosis and hypertriglyceridemia in obese mice. Overexpression of periostin resulted in reduced expression of peroxisome proliferator-activated receptor α (PPARα), a master regulator of fatty acid oxidation, and activation of the JNK signaling pathway. In mouse primary hepatocytes, inhibition of α6β4 integrin prevented activation of JNK and suppression of PPARα in response to periostin. Periostin-dependent activation of JNK resulted in activation of c-Jun, which prevented RORα binding and transactional activation at the Ppara promoter. Together, these results identify a periostin-dependent pathway that mediates obesity-induced hepatosteatosis.
肝脂肪变性的特征是肝脏中甘油三酯异常蓄积；然而，导致肥胖诱导型脂肪肝的因素在很大程度上仍不清楚。在此，我们证明分泌型细胞粘附蛋白骨膜蛋白在肥胖啮齿动物和人类的肝脏中显著上调。值得注意的是，在野生型小鼠肝脏中过表达骨膜蛋白会促进肝脂肪变性和高甘油三酯血症。相反，骨膜蛋白基因敲除和给予骨膜蛋白中和抗体均能显著改善肥胖小鼠的肝脂肪变性和高甘油三酯血症。骨膜蛋白过表达导致过氧化物酶体增殖物激活受体α（PPARα）表达降低，PPARα是脂肪酸氧化的主要调节因子，同时导致JNK信号通路激活。在小鼠原代肝细胞中，抑制α6β4整合素可防止JNK激活以及对骨膜蛋白反应时PPARα的抑制。骨膜蛋白依赖的JNK激活导致c-Jun激活，从而阻止RORα与Ppara启动子结合及转录激活。总之，这些结果确定了一条介导肥胖诱导型肝脂肪变性的骨膜蛋白依赖途径。
