PT - JOURNAL ARTICLE AU - Hongyi Zhou AU - Jie Li AU - Huabo Su AU - Ji Li AU - Todd A. Lydic AU - Martin E Young AU - Weiqin Chen TI - BSCL2/Seipin Deficiency in Heart Causes Energy Deficit and Heart Failure via Inducing Excessive Lipid Catabolism AID - 10.1101/2021.06.07.447355 DP - 2021 Jan 01 TA - bioRxiv PG - 2021.06.07.447355 4099 - http://biorxiv.org/content/early/2021/06/07/2021.06.07.447355.short 4100 - http://biorxiv.org/content/early/2021/06/07/2021.06.07.447355.full AB - Heart failure (HF) is one of the leading causes of death world-wide and is associated with cardiac metabolic perturbations. Human Type 2 Berardinelli-Seip Congenital Lipodystrophy (BSCL2) disease is caused by mutations in the BSCL2 gene. Global lipodystrophic Bscl2−/− mice exhibit hypertrophic cardiomyopathy. Whether BSCL2 plays a direct role in regulating cardiac substrate metabolism and/or contractile function remains unknown. Here we show that mice with cardiac-specific deletion of Bscl2 (Bscl2cKO) developed dilated HF. Myocardial BSCL2 deletion led to elevated ATGL expression and FA oxidation (FAO) along with reduced cardiac lipid contents. Cardiac dysfunction in Bscl2cKO mice was independent of mitochondrial dysfunction and oxidative stress, but associated with decreased metabolic reserve and ATP levels. Importantly, heart failure in Bscl2cKO mice could be partially reversed by pharmacological inhibition of FAO, or prevented by high fat diet (HFD) feeding. Lipidomic analysis further identified markedly reduced glycerolipids, glycerophospholipids, NEFA and acylcarnitines in Bscl2cKO hearts, which were partially normalized by FAO inhibition or HFD. Our study reveals a new form of HF with excessive lipid catabolism, and identifies a crucial cardiomyocyte-specific role of BSCL2 in controlling cardiac lipid catabolism, energy state and contractile function. It also provides novel insights into metabolically treating energy-starved HF using FAO inhibitor or HFD.Competing Interest StatementThe authors have declared no competing interest.