Department of Cardiology, State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
College of Life Sciences, Wuhan University, Wuhan, China.
Hepatology. 2018 Apr;67(4):1320-1338. doi: 10.1002/hep.29616. Epub 2018 Mar 2.
Nonalcoholic fatty liver disease (NAFLD) is a prevalent and complex disease that confers a high risk of severe liver disorders. Despite such public and clinical health importance, very few effective therapies are currently available for NAFLD. We report a protective function and the underlying mechanism of dual-specificity phosphatase 14 (DUSP14) in NAFLD and related metabolic disorders. Insulin resistance, hepatic lipid accumulation, and concomitant inflammatory responses, key pathological processes involved in NAFLD development, were significantly ameliorated by hepatocyte-specific DUSP14 overexpression (DUSP14-HTG) in high-fat diet (HFD)-induced or genetically obese mouse models. By contrast, specific DUSP14 deficiency in hepatocytes (DUSP14-HKO) aggravated these pathological alterations. We provided mechanistic evidence that DUSP14 directly binds to and dephosphorylates transforming growth factor β-activated kinase 1 (TAK1), resulting in the reduced activation of TAK1 and its downstream signaling molecules c-Jun N-terminal kinase 1 (JNK), p38, and nuclear factor kappa B NF-κB. This effect was further evidenced by the finding that inhibiting TAK1 activity effectively attenuated the deterioration of glucolipid metabolic phenotype in DUSP14-HKO mice challenged by HFD administration. Furthermore, we identified that both the binding domain and the phosphatase activity of DUSP14 are required for its protective role against hepatic steatosis, because interruption of the DUSP14-TAK1 interaction abolished the mitigative effects of DUSP14.
Hepatocyte DUSP14 is required for maintaining hepatic metabolic homeostasis and for suppressing inflammation, a novel function that relies on constraining TAK1 hyperactivation. (Hepatology 2018;67:1320-1338).
非酒精性脂肪性肝病（NAFLD）是一种普遍且复杂的疾病，会增加发生严重肝脏疾病的风险。尽管具有如此重要的公共卫生和临床意义，但目前针对 NAFLD 的有效治疗方法却很少。我们报告了双特异性磷酸酶 14（DUSP14）在 NAFLD 及相关代谢性疾病中的保护作用及其潜在机制。在高脂肪饮食（HFD）诱导或遗传肥胖的小鼠模型中，过表达肝细胞特异性 DUSP14（DUSP14-HTG）可显著改善胰岛素抵抗、肝脏脂质堆积以及伴随的炎症反应等关键的 NAFLD 发展病理过程。相反，特异性敲除肝细胞中的 DUSP14（DUSP14-HKO）则加剧了这些病理改变。我们提供了机制证据表明，DUSP14 可直接与转化生长因子-β激活激酶 1（TAK1）结合并使其去磷酸化，从而减少 TAK1 及其下游信号分子 c-Jun N-末端激酶 1（JNK）、p38 和核因子κB NF-κB 的激活。通过发现抑制 TAK1 活性可有效减轻 HFD 处理后 DUSP14-HKO 小鼠糖脂代谢表型的恶化，进一步证实了这一效应。此外，我们确定 DUSP14 的结合域和磷酸酶活性对于其防止肝脂肪变性的保护作用是必需的，因为 DUSP14-TAK1 相互作用的中断会消除 DUSP14 的缓解作用。
肝细胞 DUSP14 对于维持肝脏代谢稳态和抑制炎症是必需的，这是一种依赖于限制 TAK1 过度激活的新功能。（《肝脏病学》2018;67:1320-1338）
