Abstract 14505: BSCL2/Seipin Deletion Rescues ATGL-Deficiency-Induced Lethal Lipotoxic Cardiomyopathy

Abstract

Imbalances in triglyceride (TG) catabolism are associated with cardiac lipid deposition and contractile dysfunction, as manifested in patients with primary triglyceride deposit cardiomyovasculopathy (TGCV) caused by adipose triglyceride lipase (ATGL) deficiency. BSCL2/Seipin is a highly conserved endoplasmic reticulum protein widely implicated in lipid droplet biogenesis and TG metabolism. We previously reported that global Bscl2 –/– mice and mice with cardiac-specific deletion of Bscl2 manifest higher myocardial ATGL expression and develop mild cardiomyopathy with reduced cardiac steatosis. However, the interplay between BSCL2 and ATGL in hearts remains to be further interrogated. In this study, we surprisingly discovered that global BSCL2 deletion completely rescued the lethal lipotoxic cardiomyopathy in the genetic ATGL-deficient TGCV model ( Atgl –/– mice) by drastically reducing cardiac TG deposits, abolishing cardiac hypertrophy, and restoring cardiac contractility. Transcriptomic analyses identified the elevated inflammatory, oxidative stress, and extracellular matrix pathways in Atgl –/– hearts, which were dramatically ameliorated by BSCL2 deletion. Conversely, the severely suppressed cardiac metabolic functions, muscle contraction, and ion transport pathways in Atgl –/– hearts were also normalized by BSCL2 deletion. Heatmap data further revealed that the mRNA levels of Pgc1/Ppara and fatty acid oxidation (FAO) genes were not altered in Bscl2 –/– hearts but were severely repressed in Atgl –/– hearts due to defective TG lipolysis. However, their expressions in Atgl –/– Bscl2 –/– hearts were restored to similar levels as wild-type and Bscl2 –/– hearts. RT-PCR analyses further confirmed such changes. Notably, cardiac-specific deletion of BSCL2 rescues lethal cardiomyopathy in mice with cardiac-specific deletion of ATGL. These data suggest that cardiac BSCL2 cell-autonomously regulates ATGL-independent TG hydrolysis and FAO pathways essential for cardiac function. Our study highlights the presence of BSCL2-mediated ATGL-independent pathways that regulate cardiac TG metabolism and provide novel therapeutic approaches to treat ATGL-deficiency-associated lethal cardiomyopathy.