Cytosolic proteins can be selectively delivered to lysosomes for degradation 
through a type of autophagy known as chaperone-mediated autophagy (CMA). CMA 
contributes to intracellular quality control and to the cellular response to 
stress. Compromised CMA has been described in aging and in different age-related 
disorders. CMA substrates cross the lysosomal membrane through a translocation 
complex; consequently, changes in the properties of the lysosomal membrane 
should have a marked impact on CMA activity. In this work, we have analyzed the 
impact that dietary intake of lipids has on CMA activity. We have found that 
chronic exposure to a high-fat diet or acute exposure to a cholesterol-enriched 
diet both have an inhibitory effect on CMA. Lysosomes from livers of 
lipid-challenged mice had a marked decrease in the levels of the CMA receptor, 
the lysosome-associated membrane protein type 2A, because of loss of its 
stability at the lysosomal membrane. This accelerated degradation of 
lysosome-associated membrane protein type 2A, also described as the mechanism 
that determines the decline in CMA activity with age, results from its increased 
mobilization to specific lipid regions at the lysosomal membrane. Comparative 
lipidomic analyses revealed qualitative and quantitative changes in the lipid 
composition of the lysosomal membrane of the lipid-challenged animals that 
resemble those observed with age. Our findings identify a previously unknown 
negative impact of high dietary lipid intake on CMA and underscore the 
importance of diet composition on CMA malfunction in aging.