Autophagy and Lipid Homeostasis in C. elegans

<p>The worldwide prevalence of obesity, particularly in developed nations, has become an epidemic in recent decades and the trend is continuing to rise. Moreover, the prevalence of obesity in children and adolescents is rising at an alarming rate. Obesity is associated with an increased risk of metabolic disorders including heart disease, insulin resistance, type 2 diabetes and nonalcoholic fatty liver disease. Therefore it is no surprise that lipid-related metabolic disorders have become a significant burden to our healthcare system. In recent years, the conserved cellular recycling process of autophagy has been linked to several lipid-related metabolic disorders, including insulin resistance, fatty liver disease, atherosclerosis, and obesity. Autophagy plays a complex role in lipid metabolism as it contributes to both lipid storage and breakdown. The nematode C. elegans is an ideal model to address the fundamental mechanisms that underlie lipid homeostasis in an intact organism. We discovered that autophagy gene activity (unc-51/ULK1/2, bec-1/BECN1, vps-34/VPS34, and lgg-1/LC3I) is required for neutral lipid accumulation during development in C. elegans. Moreover, long-lived, daf-2/InR and glp-1/Notch loss of function mutants, characterized by increased lipid stores, also required autophagy to maintain neutral lipid accumulation. Reduced lipid levels could be due to a lack of lipid synthesis, defects in the storage, or an increase in lipid breakdown. We find that autophagy mutants are able to synthesize, store, and breakdown neutral lipids adequately, but may have an increase in lipid catabolism. Interestingly, we found the cytosolic adipose triglyceride lipase-1 (ATGL-1), is required for the reduction in lipid levels observed in autophagy mutants. Depletion of atgl-1 restored the lipid levels in several autophagy mutant backgrounds, such as unc-51/ULK1/2, bec-1/BECN1, atg-7/ATG7 and atg-16.2/ATG16L. Additionally, ATGL-1::GFP protein levels were elevated in the autophagy mutants, unc-51/ULK1 and atg-7/ATG7. Importantly, the co-activator of ATGL-1, LID-1 (in mammals, CGI-58), and the catalytic subunit of protein kinase A (PKA), KIN-1, are required for the decrease in lipid stores of autophagy-impaired animals. These data suggest that loss of autophagy results in aberrant neutral lipid levels due to dysregulation of ATGL-1 stability and/or expression. Further studies are needed to assess if the autophagy lysosomal pathway regulates ATGL-1 expression though selective degradation by autophagy. Alternatively, the autophagy machinery may control ATGL-1 localization and access to the lipid droplet as ATGL-1 contains conserved LC3 interacting region (LIR) motifs. Understanding the mechanism by which autophagy is required for lipid homeostasis is crucial to develop novel therapeutic treatments for autophagy-related metabolic disorders.</p>

Name thesis:degree_name

Doctor of Philosophy

Level thesis:degree_level

Doctoral

Discipline thesis:degree_discipline

Biology

Grantor

The Graduate School and University Center of The City University of New York

Year dc:date.available

2016

Author dc:creator

• Silvestrini, Melissa J

Advisor dc:contributor.advisor

• Alicia Melendez

Committee members dc:contributor.committeemember

• Ivica Arsov
• Cathy Savage-Dunn
• Benjamin Ortiz
• Rajat Singh

• Cell and Developmental Biology
• autophagy
• lipid homeostasis
• adipose triglyceride lipase 1 (ATGL-1)
• C. elegans

Repository record dc:identifier

https://academicworks.cuny.edu/gc_etds/1596

OAI identifier oai:identifier

oai:academicworks.cuny.edu:gc_etds-2601