Key result
Blocking lipid uptake fails to reduce cardiac lipid accumulation or prevent premature death in ATGL-deficient mice.
Why the study?
ATGL deficiency causes neutral lipid storage disease and cardiomyopathy with no current treatment, and whether reducing myocardial lipid uptake could alleviate this disorder was unknown.
Does blocking lipid uptake pathways prevent toxicity and cardiomyopathy in ATGL deficiency?
Does blocking lipid uptake pathways prevent toxicity and cardiomyopathy in ATGL deficiency?
Pathological storage of lipids and resulting cardiomyopathy in ATGL deficiency cannot be corrected by reducing heart lipid uptake, as cells compensate by increasing de novo fatty acid synthesis.
ATGL cardiomyopathy resists lipid uptake blockade in mice; leaves open de novo fatty acid synthesis inhibition as a research target.
Lipid accumulation in nonadipose tissues can cause lipotoxicity, leading to cell death and severe organ dysfunction. Adipose triglyceride lipase (ATGL) deficiency causes human neutral lipid storage 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 accumulation, 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 deficiency cannot be corrected by reducing heart lipid uptake.
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Oluwadare et al. (2022) studied ATGL deficiency-induced cardiomyopathy. Deletion of lipid uptake pathways (LpL or CD36) or dietary alteration vs. ATGL-deficient mice with intact lipid uptake pathways or standard diet was evaluated on Heart lipid accumulation, ejection fraction, and survival. Blocking lipid uptake pathways via dietary changes or genetic deletion of LpL or CD36 did not ameliorate heart lipid accumulation, cardiac dysfunction, or premature death in ATGL-deficient mice.
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