Foam Cell Induction Activates AMPK But Uncouples Its Regulation of Autophagy and Lysosomal Homeostasis

Int J Mol Sci. 2020 Nov 27;21(23):9033. doi: 10.3390/ijms21239033.


The dysregulation of macrophage lipid metabolism drives atherosclerosis. AMP-activated protein kinase (AMPK) is a master regulator of cellular energetics and plays essential roles regulating macrophage lipid dynamics. Here, we investigated the consequences of atherogenic lipoprotein-induced foam cell formation on downstream immunometabolic signaling in primary mouse macrophages. A variety of atherogenic low-density lipoproteins (acetylated, oxidized, and aggregated forms) activated AMPK signaling in a manner that was in part due to CD36 and calcium-related signaling. In quiescent macrophages, basal AMPK signaling was crucial for maintaining markers of lysosomal homeostasis as well as levels of key components in the lysosomal expression and regulation network. Moreover, AMPK activation resulted in targeted upregulation of members of this network via transcription factor EB. However, in lipid-induced macrophage foam cells, neither basal AMPK signaling nor its activation affected lysosomal-associated programs. These results suggest that while the sum of AMPK signaling in cultured macrophages may be anti-atherogenic, atherosclerotic input dampens the regulatory capacity of AMPK signaling.

Keywords: AMP-activated protein kinase (AMPK); atherosclerosis; autophagy; foam cell; immunometabolism; lipids; lysosomal homeostasis; macrophage.

MeSH terms

  • AMP-Activated Protein Kinases / metabolism*
  • Animals
  • Atherosclerosis / metabolism
  • Autophagy* / genetics
  • Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / metabolism
  • Bone Marrow Cells / metabolism
  • Bone Marrow Cells / pathology
  • CD36 Antigens / metabolism
  • Calcium-Calmodulin-Dependent Protein Kinase Kinase / metabolism
  • Cells, Cultured
  • Enzyme Activation
  • Female
  • Foam Cells / enzymology*
  • Homeostasis*
  • Lipid Metabolism
  • Lipoproteins / metabolism
  • Lysosomes / metabolism*
  • Male
  • Mice
  • Mice, Knockout
  • Signal Transduction
  • Transcription, Genetic
  • Up-Regulation / genetics


  • Basic Helix-Loop-Helix Leucine Zipper Transcription Factors
  • CD36 Antigens
  • Lipoproteins
  • Tcfeb protein, mouse
  • Calcium-Calmodulin-Dependent Protein Kinase Kinase
  • Camkk2 protein, mouse
  • AMP-Activated Protein Kinases