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Deficient chaperone-mediated autophagy in liver leads to metabolic dysregulation

Jaime L Schneider1, Yousin Suh2, Ana Maria Cuervo1

  • 1Department of Developmental and Molecular Biology, Albert Einstein College of Medicine, Bronx, NY 10461, USA; Institute for Aging Studies, Albert Einstein College of Medicine, Bronx, NY 10461, USA.

Cell Metabolism
|July 22, 2014
PubMed

Insights

Chaperone-mediated autophagy (CMA) decline with age impairs liver metabolism, causing glycogen depletion and fat accumulation. This highlights CMA

Area of Science:

  • Cellular Biology
  • Metabolism
  • Aging Research

Background:

  • Chaperone-mediated autophagy (CMA) degrades cytosolic proteins but declines with age.
  • The in vivo consequences of age-related CMA decline are not well understood.

Purpose of the Study:

  • To investigate the in vivo role of CMA in hepatic metabolism.
  • To determine the metabolic consequences of blocking CMA in the liver.

Main Methods:

  • Generated a conditional knockout mouse model to selectively block CMA in hepatocytes.
  • Utilized comparative lysosomal proteomics to identify CMA targets.
  • Assessed metabolic parameters including glucose homeostasis and energy expenditure.

Main Results:

  • CMA blockage in the liver led to hepatic glycogen depletion and hepatosteatosis.
  • Mice with impaired CMA showed reduced peripheral adiposity and increased energy expenditure.
  • Lysosomal proteomics revealed CMA degrades key metabolic enzymes, and their impaired degradation drives metabolic dysfunction.

Conclusions:

  • CMA is crucial for regulating hepatic carbohydrate and lipid metabolism.
  • Age-related decline in CMA may negatively impact the metabolic and energetic balance in aging organisms.
  • Targeting CMA could offer therapeutic strategies for age-related metabolic disorders.

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