Dual Specificity Phosphatase 12 Regulates Hepatic Lipid Metabolism Through Inhibition of the Lipogenesis and Apoptosis Signal-Regulating Kinase 1 Pathways
Dual Specificity Phosphatase 12 Regulates Hepatic Lipid Metabolism Through Inhibition of the Lipogenesis and Apoptosis Signal-Regulating Kinase 1 Pathways
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双特异性磷酸酶 12 通过抑制脂肪生成和细胞凋亡信号调节激酶 1 途径调节肝脏脂质代谢
DOI：
10.1002/hep.30597
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发表时间：
2019-10-01
期刊：
影响因子：
13.5
通讯作者：
Zhang, Yan-Zhou
中科院分区：
文献类型：
--
作者：
Huang, Zhen;Wu, Lei-Ming;Zhang, Yan-Zhou
非酒精性脂肪肝病（NAFLD）已成为全球慢性肝病的最常见原因。由于NAFLD对公共卫生造成的经济负担日益增加，它已成为临床干预的新兴目标。 DUSP12 是双特异性磷酸酶 (DUSP) 家族的成员，在棕色脂肪细胞分化、微生物感染和心脏肥大中发挥重要作用。然而，DUSP12 在 NAFLD 中的作用尚未明确。在这里，我们揭示了 DUSP12 在棕榈酸/油酸处理后可防止 L02 细胞的肝脂肪变性和炎症。我们证明肝细胞特异性 DUSP12 缺陷小鼠表现出高脂饮食 (HFD) 诱导的和高脂高胆固醇饮食诱导的高胰岛素血症和肝脏脂肪变性以及胰岛素敏感性降低。一致地，肝细胞中 DUSP12 过度表达可以减少 HFD 诱导的肝脂肪变性、胰岛素抵抗和炎症。在分子水平上，DUSP12缺失时脂肪变性的特征是凋亡信号调节激酶1（ASK1）升高，该激酶1介导丝裂原激活蛋白激酶（MAPK）途径和肝脏代谢。 DUSP12 与 ASK1 物理结合，促进其去磷酸化，并抑制其对 ASK1 相关蛋白、JUN N 末端激酶和 p38 MAPK 的作用，从而抑制高脂肪条件下的脂肪生成。结论：DUSP12 在肝脂肪变性中发挥正向调节作用，为 NAFLD 提供潜在的治疗机会。
Nonalcoholic fatty liver disease (NAFLD) has become the most common cause of chronic liver disease worldwide. Due to the growing economic burden of NAFLD on public health, it has become an emergent target for clinical intervention. DUSP12 is a member of the dual specificity phosphatase (DUSP) family, which plays important roles in brown adipocyte differentiation, microbial infection, and cardiac hypertrophy. However, the role of DUSP12 in NAFLD has yet to be clarified. Here, we reveal that DUSP12 protects against hepatic steatosis and inflammation in L02 cells after palmitic acid/oleic acid treatment. We demonstrate that hepatocyte specific DUSP12-deficient mice exhibit high-fat diet (HFD)-induced and high-fat high-cholesterol diet-induced hyperinsulinemia and liver steatosis and decreased insulin sensitivity. Consistently, DUSP12 overexpression in hepatocyte could reduce HFD-induced hepatic steatosis, insulin resistance, and inflammation. At the molecular level, steatosis in the absence of DUSP12 was characterized by elevated apoptosis signal-regulating kinase 1 (ASK1), which mediates the mitogen-activated protein kinase (MAPK) pathway and hepatic metabolism. DUSP12 physically binds to ASK1, promotes its dephosphorylation, and inhibits its action on ASK1-related proteins, JUN N-terminal kinase, and p38 MAPK in order to inhibit lipogenesis under high-fat conditions. Conclusion: DUSP12 acts as a positive regulator in hepatic steatosis and offers potential therapeutic opportunities for NAFLD.