Sarah Speck
Program: Molecular Cell Biology
Current advisor: Clay F. Semenkovich, MD
Undergraduate university: Washington University
Research summary
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.
Graduate publications
Speck SL, Wei X, Semenkovich C. 2024 Depalmitoylation and cell physiology: APT1 as a mediator of metabolic signals. Am J Physiol Cell Physiol, 326(4):C1034-C1041.
Dong G, Adak S, Spyropoulos G, Zhang Q, Feng C, Yin L, Speck SL, Shyr Z, Morikawa S, Kitamura RA, Kathayat RS, Dickinson BC, Ng XW, Piston DW, Urano F, Remedi MS, Wei X, Semenkovich CF. 2023 Palmitoylation couples insulin hypersecretion with β cell failure in diabetes. Cell Metab, 35(2):332-344.e7.
Speck SL, Bhatt DP, Zhang Q, Adak S, Yin L, Dong G, Feng C, Zhang W, Ben Major M, Wei X, Semenkovich CF.. 2023 Hepatic palmitoyl-proteomes and acyl-protein thioesterase protein proximity networks link lipid modification and mitochondria. Cell Rep, 42(11):249-65.
Wei X, Adak S, Zayed M, Yin L, Feng C, Speck SL, Kathayat RS, Zhang Q, Dickinson BC, Semenkovich C. 2020 Endothelial Palmitoylation Cycling Coordinates Vessel Remodeling in Peripheral Artery Disease. Circ Res, 127(2):249-65.