Metabolic Regulation and Obesity
Category(ies) of Research
Descriptor of Research
My research career has focused on the discovery of novel lipases that mediate the pathologic sequelae of common human diseases. Through the use of fundamental chemical principles, we have developed novel technologies that resulted in the identification of a new family of lipases, now termed patatin-like phospholipases (PNPLA1-PNPLA9)(HUGO nomenclature) due to their extensive homology with a protein that is abundant in plants that is essential for the regulation of energy metabolism and signaling. Early studies identified the prominent role of three members of the PNPLA family in mediating alterations in lipid metabolism and membrane function in diabetic hearts. These included the discovery of PNPLA9 as a mediator of ischemia-induced ventricular arrhythmias and PNPLA8 as an important regulator of mitochondrial bioenergetics and apoptosis in diabetic myocardium. Moreover, in 2004 we identified PNPLA2 (also known as ATGL) as the major triglyceride lipase in myocardium whose activity modulates the accumulation of triglycerides and lipotoxicity in diabetic myocardium. In addition, we discovered two novel triglyceride lipases homologous to patatin (PNPLA3 and PNPLA4) that catalyze both triglyceride lipase activity and transacylase activity further defining the complex alterations in lipid metabolism in diabetic myocardium. Recently, we used homologous recombination to genetically ablate iPLA2 leading to the generation of animals that demonstrated multiple defects in myocardial mitochondrial function and maladaptive alterations to cardiac stress. Finally, our laboratory has developed multidimensional mass spectrometry which has provided an essential tool in defining the functional alterations in lipid metabolism that promote the progression of heart failure in diabetic cardiomyopathy (e.g., cardiolipin remodeling). Through the synergistic use of unique genetic reagents we have constructed, in conjunction with the novel mass spectrometric technologies we developed, a detailed understanding of the roles of the PNPLA family of enzymes in diabetic cardiomyopathy can be uncovered.