Autophagy is an evolutionarily conserved pathway that recycles organelles and long-lived proteins to supply energy and maintain cellular homeostasis. In mammals, autophagy has been shown to be involved in both lipid storage and lipid breakdown, and defects in autophagy have been linked to metabolic disorders including fatty liver disease, atherosclerosis and obesity. Moreover, adequate energy reservoirs are essential for the survival, growth and reproduction of animals. Our lab has shown that autophagy is required for lipid accumulation during C. elegans development. The decrease in lipid content in autophagy gene mutant animals could be due to deficient lipid synthesis, defects in recycling/storage of lipids, or increased breakdown of lipids.
bec-1,
atg-7 and
atg-16.2 loss-of-function mutants are able to synthesize and store lipid droplets during "lipid loading" conditions, suggesting that autophagy genes are not required for the synthesis or storage of lipid droplets. In addition, short-term fasting further reduced lipid levels in autophagy gene mutant animals (
bec-1,
atg-7 and
atg-16.2), indicating that mobilization and breakdown of lipids can occur in these mutant animals. In a candidate screen for specific lipases involved in the lipid loss phenotype observed in autophagy mutants, we found that the evolutionarily conserved adipose triglyceride lipase 1 (ATGL-1) is required for the breakdown of lipids observed in
atg-7 or
atg-16.2 loss-of-function mutants. Depletion of
atgl-1 by RNAi suppressed the decrease in lipids observed in
atg-7 and
atg-16.2 mutants. Moreover, RNAi depletion of
lid-1 (CGI-58 in mammals), the co-activator of ATGL-1, also suppresses lipid loss in autophagy gene mutant animals. Furthermore, ATGL-1::GFP expression was found to be 60% increased in
atg-7 mutants compared to wild-type animals. Thus, an increase in ATGL-1 lipase expression may result in the low-fat phenotype in the autophagy
atg-7 and
atg-16.2 mutant animals. We are working to determine which genes act upstream to regulate lipid mobilization in autophagy mutants and will report on our progress. Understanding the cellular mechanisms by which autophagy contributes to lipid homeostasis is crucial to develop novel therapeutic approaches to treat autophagy-related lipid and metabolic disorders.