Abstract

Tens of millions of Americans suffer from metabolic disorders, predisposing patients to cardiovascular disease, kidney disease, liver disease, infertility, and cancer. Unfortunately, the etiology of many of these diseases remains a mystery, limiting our ability to identify targets for pharmacologic therapies. Due to the relationship between altered lipid dynamics and metabolic dysfunction, we decided to study the effect of the posttranslational lipid modification, S-palmitoylation, on metabolism. S-palmitoylation is the only known reversible lipid modification for proteins, and this depalmitoylation process is catalyzed by acyl-protein thioesterases including APT1 and APT2. We hypothesized that APT deficiency in various tissues would predispose mammals to metabolic disease. We generated mice with APT deficiency in endothelial cells, pancreatic beta cells, or the liver. We found that endothelial APT1 deficiency impaired recovery of perfusion in a mouse model of peripheral artery disease. Next, we discovered that APT1-deficient beta cells hypersecrete insulin, which leads to early beta cell failure in genetic and dietary models of type 2 diabetes. We then determined that hepatic APT1 and APT2 regulate insulin sensitivity and glutamine-induced gluconeogenesis, as well as mitochondrial respiration. In each of these studies, we identified several novel APT substrates, as well as new pathways for upstream regulation of APT activity. These findings establish depalmitoylases as critical mediators of metabolic signaling and potential targets for novel therapies.

Committee Chair

Clay Semenkovich

Committee Members

Brian Finck; David Piston; Irfan Lodhi; Michael Major; Nada Abumrad

Degree

Doctor of Philosophy (PhD)

Author's Department

Biology & Biomedical Sciences (Molecular Cell Biology)

Author's School

Graduate School of Arts and Sciences

Document Type

Dissertation

Date of Award

5-8-2025

Language

English (en)

Author's ORCID

https://orcid.org/0000-0002-3059-1847

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