Adipose triglyceride lipase (ATGL) (ATGL)

Adipose triglyceride lipase (ATGL), encoded by the PNPLA2 gene, is the rate-limiting enzyme responsible for the initial step of triglyceride hydrolysis in the heart, a process known as myocardial lipolysis (UniProt P0C612). It catalyzes the conversion of triacylglycerols to diacylglycerols, releasing long-chain fatty acids that serve as the primary fuel source for cardiac oxidative metabolism (Haemmerle et al., 2006). Proper regulation of this pathway is crucial for cardiac health; mutations leading to ATGL deficiency cause Neutral Lipid Storage Disease with Myopathy (NLSDM), which is characterized by severe cardiac steatosis and progressive heart failure (OMIM 610717). Conversely, pathologically increased myocardial lipolysis is associated with lipotoxicity and the development of diabetic cardiomyopathy (Zechner et al., 2012). Pharmacological inhibitors like Atglistatin have been developed to study the therapeutic potential of reducing fatty acid mobilization in metabolic diseases (Schreiber et al., 2017). While targeting ATGL offers a potential route to treat lipid-related cardiac dysfunction, systemic inhibition carries risks of ectopic lipid accumulation in skeletal muscle and the liver. The enzyme's activity is further regulated by co-activators like CGI-58 and inhibitors like G0S2, which are also potential points of therapeutic intervention.

Other names

Patatin-like phospholipase domain-containing protein 2PNPLA2DesnutrinTriglyceride hydrolaseiPLA2-zetaMyocardial lipolysis

Inhibition of the enzyme to reduce the hydrolysis of triglycerides into fatty acids, thereby preventing lipotoxicity or modulating energy substrate availability.