Depalmitoylation and cell physiology: APT1 as a mediator of metabolic signals.

More than half of the global population is obese or overweight, especially in Western countries, and this excess adiposity disrupts normal physiology to cause chronic diseases. Diabetes, an adiposity-associated epidemic disease, affects >500 million people, and cases are projected to exceed 1 billion before 2050. Lipid excess can impact physiology through the posttranslational modification of proteins, including the reversible process of S-palmitoylation.

Hepatic palmitoyl-proteomes and acyl-protein thioesterase protein proximity networks link lipid modification and mitochondria.

Acyl-protein thioesterases 1 and 2 (APT1 and APT2) reverse S-acylation, a potential regulator of systemic glucose metabolism in mammals. Palmitoylation proteomics in liver-specific knockout mice shows that APT1 predominates over APT2, primarily depalmitoylating mitochondrial proteins, including proteins linked to glutamine metabolism. miniTurbo-facilitated determination of the protein-protein proximity network of APT1 and APT2 in HepG2 cells reveals APT proximity networks encompassing mitochondrial proteins including the major translocases Tomm20 and Timm44.

Palmitoylation couples insulin hypersecretion with β cell failure in diabetes.

Hyperinsulinemia often precedes type 2 diabetes. Palmitoylation, implicated in exocytosis, is reversed by acyl-protein thioesterase 1 (APT1). APT1 biology was altered in pancreatic islets from humans with type 2 diabetes, and APT1 knockdown in nondiabetic islets caused insulin hypersecretion.

Endothelial Palmitoylation Cycling Coordinates Vessel Remodeling in Peripheral Artery Disease.

Rationale: Peripheral artery disease, common in metabolic syndrome and diabetes mellitus, responds poorly to medical interventions and is characterized by chronic vessel immaturity leading to lower extremity amputations.

Objective: To define the role of reversible palmitoylation at the endothelium in the maintenance of vascular maturity.

Methods And Results: Endothelial knockout of the depalmitoylation enzyme APT-1 (acyl-protein thioesterase 1) in mice impaired recovery from chronic hindlimb ischemia, a model of peripheral artery disease.