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Exploring the Regulation of Lipid Droplet Catabolism through Lipophagy

Exploring the Regulation of Lipid Droplet Catabolism through Lipophagy

Published on: January 31, 2025

Protective role of chaperone-mediated autophagy against atherosclerosis

Julio Madrigal-Matute^1,2, Jenny de Bruijn³, Kim van Kuijk^3,4

¹Department of Development and Molecular Biology, Albert Einstein College of Medicine, Bronx, NY 10461.

Proceedings of the National Academy of Sciences of the United States of America

|April 1, 2022

Abstract:

Chaperone-mediated autophagy (CMA) contributes to regulation of energy homeostasis by timely degradation of enzymes involved in glucose and lipid metabolism. Here, we report reduced CMA activity in vascular smooth muscle cells and macrophages in murine and human arteries in response to atherosclerotic challenges. We show that in vivo genetic blockage of CMA worsens atherosclerotic pathology through both systemic and cell-autonomous changes in vascular smooth muscle cells and macrophages, the two main cell types involved in atherogenesis. CMA deficiency promotes dedifferentiation of vascular smooth muscle cells and a proinflammatory state in macrophages. Conversely, a genetic mouse model with up-regulated CMA shows lower vulnerability to proatherosclerotic challenges. We propose that CMA could be an attractive therapeutic target against cardiovascular diseases.

Insights

Reduced chaperone-mediated autophagy (CMA) activity worsens atherosclerosis by affecting vascular smooth muscle cells and macrophages. Boosting CMA may offer a new therapeutic strategy for cardiovascular diseases.

Area of Science:

Cellular biology
Metabolic regulation
Cardiovascular research

Background:

Chaperone-mediated autophagy (CMA) regulates energy homeostasis through enzyme degradation.
CMA's role in atherosclerosis, particularly in vascular cells and macrophages, is not fully understood.

Purpose of the Study:

To investigate the role of CMA in the pathogenesis of atherosclerosis.
To determine if CMA modulation affects atherosclerotic plaque development and cellular behavior.

Main Methods:

Assessing CMA activity in murine and human arteries under atherosclerotic conditions.
Utilizing genetic models with blocked or upregulated CMA in vivo.
Analyzing changes in vascular smooth muscle cells and macrophages in response to CMA manipulation.

Main Results:

CMA activity is reduced in vascular smooth muscle cells and macrophages during atherosclerosis.
Genetic blockage of CMA exacerbates atherosclerotic pathology and promotes vascular smooth muscle cell dedifferentiation and macrophage inflammation.
Upregulated CMA reduces susceptibility to proatherosclerotic challenges.

Conclusions:

CMA plays a critical protective role in preventing atherosclerosis.
CMA deficiency promotes key cellular changes that drive atherogenesis.
CMA represents a potential therapeutic target for cardiovascular diseases.

Read full analysis

Keywords:

atherosclerotic plaques lipid challenge lysosomes proteolysis vascular disease

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