Macrophage STING-YAP axis controls hepatic steatosis by promoting autophagic degradation of lipid droplets

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 beta-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 AMPK alpha, which interacts with hepatocyte mitofusin 2 (MFN2) and induces protein disulfide isomerase (PDI) activation. PDI activates hypoxia-inducible factor-1 alpha (HIF-1 alpha) 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.