HSPA12A Is a Novel Player in Nonalcoholic Steatohepatitis via Promoting Nuclear PKM2-Mediated M1 Macrophage Polarization
HSPA12A Is a Novel Player in Nonalcoholic Steatohepatitis via Promoting Nuclear PKM2-Mediated M1 Macrophage Polarization
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HSPA12A 通过促进核 PKM2 介导的 M1 巨噬细胞极化，成为非酒精性脂肪性肝炎的新参与者
DOI：
10.2337/db18-0035
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发表时间：
2019-02-01
期刊：
影响因子：
7.7
通讯作者：
Ding, Zhengnian
中科院分区：
文献类型：
--
作者：
Kong, Qiuyue;Li, Nan;Ding, Zhengnian
非酒精性脂肪性肝炎（NASH）是全球慢性肝病最常见的原因。巨噬细胞介导的炎症在NASH发病机制中起关键作用;然而，巨噬细胞活化和NASH的最佳疗法仍然难以捉摸。HSPA 12 A编码HSP 70家族的新成员。在此，我们报告NASH患者显示肝HSPA 12 A表达和血清HSPA 12 A含量增加。有趣的是，敲除小鼠中的HSPA 12 A（Hspa 12 a（-/-））减轻了高脂饮食（HFD）诱导的肝脂肪变性和损伤。HFD诱导的巨噬细胞向M1表型极化和Hspa 12 a（-/-）小鼠肝脏中的炎症反应也减弱。功能丧失和获得研究表明，肝细胞中的从头脂肪生成是由巨噬细胞HSPA 12 A的旁分泌效应调节的，而不是由肝细胞HSPA 12 A调节的。深入的分子分析显示，HSPA 12 A与巨噬细胞中丙酮酸激酶（PKM 2）的M2亚型相互作用，并增加其核转位，从而促进M1极化和促炎性M1细胞因子的分泌;这最终通过旁分泌效应导致肝细胞脂肪变性。总之，这些发现表明，HSPA 12 A通过增加核PKM 2作为M1巨噬细胞极化和NASH发病机制的新调节剂。抑制巨噬细胞HSPA 12 A的策略可能是NASH的潜在治疗干预。
Nonalcoholic steatohepatitis (NASH) is the most prevalent cause of chronic liver disease worldwide. Macrophage-mediated inflammation plays a critical role in NASH pathogenesis; however, optimum therapies for macrophage activation and NASH remain elusive. HSPA12A encodes a novel member of the HSP70 family. Here, we report that NASH patients showed increased hepatic HSPA12A expression and serum HSPA12A contents. Intriguingly, knockout of HSPA12A (Hspa12a(-/-)) in mice attenuated high-fat diet (HFD)-induced hepatic steatosis and injury. HFD-induced macrophage polarization toward an M1 phenotype and inflammatory responses in the liver of Hspa12a(-/-) mice were also attenuated. Loss- and gain-of-function studies revealed that the de novo lipogenesis in hepatocytes was regulated by the paracrine effects of macrophage HSPA12A rather than by hepatocyte HSPA12A. In-depth molecular analysis revealed that HSPA12A interacted with the M2 isoform of pyruvate kinase (PKM2) in macrophages and increased its nuclear translocation, thereby promoting M1 polarization and secretion of proinflammatory M1 cytokines; this led, ultimately, to hepatocyte steatosis via paracrine effects. Taken together, these findings show that HSPA12A acts as a novel regulator of M1 macrophage polarization and NASH pathogenesis by increasing nuclear PKM2. Strategies that inhibit macrophage HSPA12A might be a potential therapeutic intervention for NASH.