BACKGROUND AIMS The hallmark of nonalcoholic fatty liver disease (NAFLD) or hepatic steatosis is characterized by lipid droplet (LD) accumulation in hepatocytes. Autophagy may have profound effects on lipid metabolism and innate immune response. However, how innate immune activation may regulate the autophagic degradation of intracellular LDs remains elusive. APPROACH RESULTS A mouse model of a high-fat diet (HFD)-induced NASH was used in the myeloid-specific STING knockout (STINGM-KO) or STING/YAP double knockout (STING/YAPDKO) mice. Liver injury, lipid accumulation, lipid droplet proteins, autophagic genes, chromatin immunoprecipitation coupled with massively parallel sequencing (ChIP-Seq), and RNA-Seq were assessed in vivo and in vitro. We found that HFD-induced oxidative stress activates STING and YAP pathways in hepatic macrophages. Macrophage STING deficiency (STINGM-KO) enhances nuclear YAP activity, reduces lipid accumulation, and increases autophagy-related protein ATG5, ATG7, and LC3B but diminishes LD protein perilipin 2 (PLIN2) expression. However, disruption of STING and YAP (STING/YAPM-DKO) increases serum ALT and TG levels, reduces β-fatty acid oxidation gene expression but augments PLIN2 levels, exacerbating HFD-induced lipid deposition. ChIP-Seq reveals that macrophage YAP targets transmembrane protein 205 (TMEM205) and activates AMPKα, which interacts with hepatocyte mitofusin 2 (MFN2) and induces protein disulfide isomerase (PDI) activation. PDI activates hypoxia-inducible factor-1α (HIF-1α) signaling, increases autophagosome colocalization with LDs, promotes the degradation of PLIN2 by interacting with chaperone-mediated autophagy (CMA) chaperone HSC70. CONCLUSION Macrophage STING-YAP axis controls hepatic steatosis by reprogramming lipid metabolism in a TMEM205/MFN2/PDI-dependent pathway. These findings highlight the regulatory mechanism of macrophage STING-driven YAP activity on lipid control.

中文翻译：

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巨噬细胞 STING-YAP 轴通过促进脂滴的自噬降解来控制肝脂肪变性。

背景目的非酒精性脂肪性肝病(NAFLD)或肝脂肪变性的特征是肝细胞中脂滴(LD)积聚。自噬可能对脂质代谢和先天免疫反应产生深远的影响。然而，先天免疫激活如何调节细胞内 LD 的自噬降解仍不清楚。方法结果 高脂饮食 (HFD) 诱导的 NASH 小鼠模型用于骨髓特异性 STING 敲除 (STINGM-KO) 或 STING/YAP 双敲除 (STING/YAPDKO) 小鼠。在体内和体外评估了肝损伤、脂质积累、脂滴蛋白、自噬基因、染色质免疫沉淀结合大规模并行测序 (ChIP-Seq) 和 RNA-Seq。我们发现 HFD 诱导的氧化应激激活肝巨噬细胞中的 STING 和 YAP 通路。巨噬细胞 STING 缺陷 (STINGM-KO) 会增强核 YAP 活性，减少脂质积累，并增加自噬相关蛋白 ATG5、ATG7 和 LC3B，但会减少 LD 蛋白 perilipin 2 (PLIN2) 的表达。然而，STING 和 YAP (STING/YAPM-DKO) 的破坏会增加血清 ALT 和 TG 水平，降低 β-脂肪酸氧化基因表达，但会增加 PLIN2 水平，加剧 HFD 诱导的脂质沉积。ChIP-Seq 揭示巨噬细胞 YAP 靶向跨膜蛋白 205 (TMEM205) 并激活 AMPKα，AMPKα 与肝细胞线粒体融合蛋白 2 (MFN2) 相互作用并诱导蛋白二硫键异构酶 (PDI) 激活。PDI 激活缺氧诱导因子 1α (HIF-1α) 信号传导，增加自噬体与 LD 的共定位，通过与伴侣介导的自噬 (CMA) 伴侣 HSC70 相互作用促进 PLIN2 的降解。结论 巨噬细胞 STING-YAP 轴通过在 TMEM205/MFN2/PDI 依赖性途径中重编程脂质代谢来控制肝脂肪变性。这些发现强调了巨噬细胞 STING 驱动的 YAP 活性对脂质控制的调节机制。