Blocking Lipid Uptake Pathways Does not Prevent Toxicity in Adipose Triglyceride Lipase (ATGL) Deficiency

Lipid accumulation in nonadipose tissues can cause lipotoxicity, leading to cell death and se- vere organ dysfunction. Adipose triglyceride lipase (ATGL) deficiency causes human neutral lipid stor- age disease and leads to cardiomyopathy; ATGL deficiency has no current treatment. One possible approach to alleviate this disorder has been to alter the diet and reduce the supply of dietary lipids and, hence, myocardial lipid uptake. However, in this study, when we supplied cardiac Atgl KO mice a low - or high-fat diet, we found that heart lipid accumula- tion, heart dysfunction, and death were not altered. We next deleted lipid uptake pathways in the ATGL- deficient mice through the generation of double KO mice also deficient in either cardiac lipoprotein lipase or cluster of differentiation 36, which is involved in an lipoprotein lipase-independent pathway for FA uptake in the heart. We show that neither deletion ameliorated ATGL-deficient heart dysfunction. Similarly, we determined that non-lipid-containing media did not prevent lipid accumulation by cultured myocytes; rather, the cells switched to increased de novo FA synthesis. Thus, we conclude that pathological storage of lipids in ATGL defi- ciency cannot be corrected by reducing heart lipid uptake.

Automated summary

This study reveals that altering the diet and reducing cardiac lipid uptake cannot alleviate heart dysfunction and lipid accumulation caused by ATGL deficiency. Deleting lipid uptake pathways in ATGL-deficient mice also fails to improve heart dysfunction.