Deficient Chaperone-Mediated Autophagy in Liver Leads to Metabolic Dysregulation

• Published in: Cell metabolism Vol. 20; no. 3; pp. 417 - 432
• Main Authors: Schneider, Jaime L., Suh, Yousin, Cuervo, Ana Maria
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 02.09.2014
• Subjects: Animals; Autophagy; Carbohydrate Metabolism; Fatty Liver - genetics; Fatty Liver - metabolism; Fatty Liver - pathology; Female; Homeostasis; Lipid Metabolism; Liver - metabolism; Liver - pathology; Lysosomal-Associated Membrane Protein 2 - genetics; Lysosomal-Associated Membrane Protein 2 - metabolism; Male; Mice; Mice, Knockout
• ISSN: 1550-4131; 1932-7420
• DOI: 10.1016/j.cmet.2014.06.009

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. [Display omitted] •Blockage of liver CMA leads to hepatosteatosis and altered glucose metabolism•Hepatic CMA failure has a negative impact on the whole-body energetic balance•Metabolic enzymes are a major component of the subproteome degraded by CMA•CMA degradation of metabolic enzymes contributes to regulation of metabolism Schneider et al. show that loss of LAMP-2A, the limiting component of chaperone-mediated autophagy (CMA), in the liver results in perturbations in hepatic carbohydrate and lipid metabolism. CMA selectively degrades enzymes in carbohydrate and lipid metabolism, and failure of CMA, as occurs with age, may underlie the associated metabolic dysregulation.