Palmitic acid dysregulates the Hippo-YAP pathway and inhibits angiogenesis by inducing mitochondrial damage and activating the cytosolic DNA sensor cGAS-STING-IRF3 signaling mechanism

J Biol Chem. 2017 Sep 8;292(36):15002-15015. doi: 10.1074/jbc.M117.804005. Epub 2017 Jul 11.


Impaired angiogenesis and wound healing carry significant morbidity and mortality in diabetic patients. Metabolic stress from hyperglycemia and elevated free fatty acids have been shown to inhibit endothelial angiogenesis. However, the underlying mechanisms remain poorly understood. In this study, we show that dysregulation of the Hippo-Yes-associated protein (YAP) pathway, an important signaling mechanism in regulating tissue repair and regeneration, underlies palmitic acid (PA)-induced inhibition of endothelial angiogenesis. PA inhibited endothelial cell proliferation, migration, and tube formation, which were associated with increased expression of mammalian Ste20-like kinases 1 (MST1), YAP phosphorylation/inactivation, and nuclear exclusion. Overexpression of YAP or knockdown of MST1 prevented PA-induced inhibition of angiogenesis. When searching upstream signaling mechanisms, we found that PA dysregulated the Hippo-YAP pathway by inducing mitochondrial damage. PA treatment induced mitochondrial DNA (mtDNA) release to cytosol, and activated cytosolic DNA sensor cGAS-STING-IRF3 signaling. Activated IRF3 bound to the MST1 gene promoter and induced MST1 expression, leading to MST1 up-regulation, YAP inactivation, and angiogenesis inhibition. Thus, mitochondrial damage and cytosolic DNA sensor cGAS-STING-IRF3 signaling are critically involved in PA-induced Hippo-YAP dysregulation and angiogenesis suppression. This mechanism may have implication in impairment of angiogenesis and wound healing in diabetes.

Keywords: Hippo pathway; MST1 (mammalian sterile 20-like kinase 1); Yes-associated protein (YAP); angiogenesis; diabetes; interferon regulatory factor (IRF); mitochondrial DNA damage; wound healing.

MeSH terms

  • Adaptor Proteins, Signal Transducing / metabolism*
  • Cell Movement / drug effects
  • Cell Proliferation / drug effects
  • Cells, Cultured
  • Dose-Response Relationship, Drug
  • Hippo Signaling Pathway
  • Humans
  • Interferon Regulatory Factor-3 / metabolism*
  • Membrane Proteins / metabolism*
  • Mitochondria / drug effects
  • Mitochondria / metabolism
  • Mitochondria / pathology*
  • Neovascularization, Pathologic / drug therapy*
  • Neovascularization, Pathologic / metabolism
  • Nucleotidyltransferases / metabolism*
  • Palmitic Acid / pharmacology*
  • Phosphoproteins / metabolism*
  • Protein Serine-Threonine Kinases / metabolism*
  • Signal Transduction / drug effects
  • Structure-Activity Relationship
  • Transcription Factors
  • YAP-Signaling Proteins


  • Adaptor Proteins, Signal Transducing
  • IRF3 protein, human
  • Interferon Regulatory Factor-3
  • Membrane Proteins
  • Phosphoproteins
  • STING1 protein, human
  • Transcription Factors
  • YAP-Signaling Proteins
  • YAP1 protein, human
  • Palmitic Acid
  • Protein Serine-Threonine Kinases
  • Nucleotidyltransferases
  • cGAS protein, human