Department of Surgery, The Dumont-UCLA Transplant Center, Division of Liver and Pancreas Transplantation, David Geffen School of Medicine at UCLA, Los Angeles, California, USA.
Department of Infectious Diseases, The First Affiliated Hospital, Nanjing Medical University, Nanjing, China.
Hepatology. 2024 Nov 1;80(5):1169-1183. doi: 10.1097/HEP.0000000000000638. Epub 2023 Oct 23.
The hallmark of 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.
A mouse model of a high-fat diet-induced NASH was used in the myeloid-specific stimulator of interferon genes (STING) knockout or STING/yes-associated protein (YAP) double knockout mice. Liver injury, lipid accumulation, lipid droplet proteins, autophagic genes, chromatin immunoprecipitation coupled with massively parallel sequencing, and RNA-Seq were assessed in vivo and in vitro . We found that high-fat diet-induced oxidative stress activates STING and YAP pathways in hepatic macrophages. The acrophage STING deficiency (myeloid-specific STING knockout) enhances nuclear YAP activity, reduces lipid accumulation, and increases autophagy-related proteins ATG5, ATG7, and light chain 3B but diminishes LD protein perilipin 2 expression. However, disruption of STING and YAP (myeloid STING and YAP double knockout) increases serum alanine aminotransferase and triglyceride levels and reduces β-fatty acid oxidation gene expression but augments perilipin 2 levels, exacerbating high-fat diet-induced lipid deposition. Chromatin immunoprecipitation coupled with massively parallel sequencing reveals that macrophage YAP targets transmembrane protein 205 and activates AMP-activated protein kinase α, which interacts with hepatocyte mitofusin 2 and induces protein disulfide isomerase activation. Protein disulfide isomerase activates hypoxia-inducible factor-1α signaling, increases autophagosome colocalization with LDs, and promotes the degradation of perilipin 2 by interacting with chaperone-mediated autophagy chaperone HSC70.
The macrophage STING-YAP axis controls hepatic steatosis by reprogramming lipid metabolism in a transmembrane protein 205/mitofusin 2/protein disulfide isomerase-dependent pathway. These findings highlight the regulatory mechanism of the macrophage STING-driven YAP activity on lipid control.
非酒精性脂肪性肝病（NAFLD）或肝脂肪变性的标志是肝细胞中脂质滴（LD）的积累。自噬可能对脂质代谢和固有免疫反应有深远的影响。然而，固有免疫激活如何调节细胞内 LD 的自噬降解仍不清楚。
使用高脂饮食诱导的 NASH 小鼠模型，在髓系特异性干扰素基因刺激物（STING）敲除或 STING/yes 相关蛋白（YAP）双敲除小鼠中进行研究。在体内和体外评估肝损伤、脂质积累、脂滴蛋白、自噬基因、染色质免疫沉淀与大规模平行测序以及 RNA-Seq。我们发现，高脂饮食诱导的氧化应激激活了肝巨噬细胞中的 STING 和 YAP 途径。巨噬细胞 STING 缺乏（髓系特异性 STING 敲除）增强了核 YAP 活性，减少了脂质积累，增加了自噬相关蛋白 ATG5、ATG7 和 LC3B，但减少了 LD 蛋白 perilipin 2 的表达。然而，STING 和 YAP 的破坏（髓系 STING 和 YAP 双敲除）增加了血清丙氨酸氨基转移酶和甘油三酯水平，降低了β-脂肪酸氧化基因的表达，但增加了 perilipin 2 的水平，加剧了高脂饮食诱导的脂质沉积。染色质免疫沉淀与大规模平行测序显示，巨噬细胞 YAP 靶向跨膜蛋白 205，并激活 AMP 激活的蛋白激酶α，与肝细胞融合蛋白 2 相互作用，并诱导蛋白二硫键异构酶的激活。蛋白二硫键异构酶激活缺氧诱导因子-1α信号通路，增加自噬体与 LD 的共定位，并通过与伴侣介导的自噬伴侣 HSC70 相互作用促进 perilipin 2 的降解。
巨噬细胞 STING-YAP 轴通过跨膜蛋白 205/融合蛋白 2/蛋白二硫键异构酶依赖性途径重塑脂质代谢，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。
