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Cell Metab. 2014 Sep 2;20(3):417-32. doi: 10.1016/j.cmet.2014.06.009. Epub 2014 Jul 17.

Deficient chaperone-mediated autophagy in liver leads to metabolic dysregulation.

Author information

1
Department 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.
2
Institute for Aging Studies, Albert Einstein College of Medicine, Bronx, NY 10461, USA; Department of Molecular Genetics, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
3
Department 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. Electronic address: ana-maria.cuervo@einstein.yu.edu.

Abstract

The activity of chaperone-mediated autophagy (CMA), a catabolic pathway for selective degradation of cytosolic proteins in lysosomes, decreases with age, but the consequences of this functional decline in vivo remain unknown. In this work, we have generated a conditional knockout mouse to selectively block CMA in liver. We have found that blockage of CMA causes hepatic glycogen depletion and hepatosteatosis. The liver phenotype is accompanied by reduced peripheral adiposity, increased energy expenditure, and altered glucose homeostasis. Comparative lysosomal proteomics revealed that key enzymes in carbohydrate and lipid metabolism are normally degraded by CMA and that impairment of their regulated degradation contributes to the metabolic abnormalities observed in CMA-defective animals. These findings highlight the involvement of CMA in regulating hepatic metabolism and suggest that the age-related decline in CMA may have a negative impact on the energetic balance in old organisms.

Comment in

PMID:
25043815
PMCID:
PMC4156578
DOI:
10.1016/j.cmet.2014.06.009
[Indexed for MEDLINE]
Free PMC Article

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