The macrophage STING-YAP axis controls hepatic steatosis by promoting the autophagic degradation of lipid droplets

作者：Tao Yang, Xiaoye Qu, Xiao Wang, Dongwei Xu, Mingwei Sheng, Yuanbang Lin, Michael Ke, Ci Song, Qiang Xia, Longfeng Jiang, Jun Li, Douglas G. Farmer, Bibo Ke · 发表于：Hepatology · 年份：2023 · DOI：10.1097/hep.0000000000000638 · 被引用次数：51 · 研究领域：Lipid metabolism and biosynthesis、interferon and immune responses、Autophagy in Disease and Therapy

BACKGROUND AND AIMS: 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. APPROACH AND RESULTS: 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 pr...