Deficient Chaperone-Mediated Autophagy Promotes Lipid Accumulation in Macrophage

J Cardiovasc Transl Res. 2021 Aug;14(4):661-669. doi: 10.1007/s12265-020-09986-3. Epub 2020 Apr 13.

Abstract

Chaperone-mediated autophagy (CMA) serves as a critical upstream regulator of lipophagy and lipid metabolism in hepatocyte. However, the role of CMA in lipid metabolism of macrophage, the typical component of atherosclerotic plaque, remains unclear. In our study, LAMP-2A (L2A, a CMA marker) was reduced in macrophages exposed to high dose of oleate, and lipophagy was impaired in advanced atherosclerosis in ApoE (-/-) mice. Primary peritoneal macrophages isolated from macrophage-specific L2A-deficient mice exhibited pronounced intracellular lipid accumulation. Lipid regulatory enzymes, including long-chain-fatty-acid-CoA ligase 1 (ACSL1) and lysosomal acid lipase (LAL), were increased and reduced in L2A-KO macrophage, respectively. Other lipid-related proteins, such as SR-A, SR-B (CD36), ABCA1, or PLIN2, were not associated with increased lipid content in L2A-KO macrophage. In conclusion, deficient CMA promotes lipid accumulation in macrophage probably by regulating enzymes involved in lipid metabolism. CMA may represent a novel therapeutic target to alleviate atherosclerosis by promoting lipid metabolism. Graphical abstract.

Keywords: Atherosclerosis; Chaperone-mediated autophagy; Lipid metabolism; Long-chain-fatty-acid-CoA ligase 1; Lysosomal acid lipase.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Atherosclerosis / genetics
  • Atherosclerosis / metabolism*
  • Atherosclerosis / pathology
  • Autophagy* / drug effects
  • Cells, Cultured
  • Coenzyme A Ligases / metabolism
  • Disease Models, Animal
  • Lipid Metabolism* / drug effects
  • Lysosomal-Associated Membrane Protein 2 / genetics
  • Lysosomal-Associated Membrane Protein 2 / metabolism*
  • Macrophages, Peritoneal / drug effects
  • Macrophages, Peritoneal / metabolism*
  • Macrophages, Peritoneal / pathology
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout, ApoE
  • Oleic Acid / toxicity
  • Sterol Esterase / metabolism

Substances

  • LAMP2 protein, human
  • Lysosomal-Associated Membrane Protein 2
  • Oleic Acid
  • Sterol Esterase
  • lysosomal acid lipase, mouse
  • ACSL1 protein, mouse
  • Coenzyme A Ligases