Deficient chaperone-mediated autophagy in liver leads to metabolic dysregulation

Jaime L. Schneider, Yousin Suh, Ana Maria Cuervo

Research output: Contribution to journalArticle

119 Scopus citations

Abstract

Summary 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.

Original languageEnglish (US)
Pages (from-to)417-432
Number of pages16
JournalCell metabolism
Volume20
Issue number3
DOIs
StatePublished - Sep 2 2014

ASJC Scopus subject areas

  • Physiology
  • Molecular Biology
  • Cell Biology

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