Lipid droplets (LDs) are multifunctional organelles that regulate energy storage and cellular homeostasis. The first step of triacylglycerol (TAG) hydrolysis in LDs is catalyzed by adipose triglyceride lipase (ATGL), deficiency of which results in lethal cardiac steatosis. Although hormone-sensitive lipase (HSL) functions as a diacylglycerol (DAG) lipase in the heart, we hypothesized that activation of HSL might compensate for ATGL deficiency. To test this hypothesis, we crossed ATGL-knockout (KO) mice and cardiac-specific HSL-overexpressing mice (cHSL) to establish homozygous ATGL-KO (AKO) mice and AKO mice with cardiac-specific HSL overexpression (AKO+cHSL). We found that cardiac TAG content was 160-fold higher in AKO relative to wild type (Wt) mice, while that of AKO+cHSL mice was comparable to the latter. In addition, AKO cardiac tissues exhibited reduced mRNA expression of PPARalpha-regulated genes, and upregulation of genes involved in inflammation, fibrosis, and cardiac stress. In contrast, AKO+cHSL cardiac tissues exhibited expression levels similar to those observed in Wt mice. AKO cardiac tissues also exhibited macrophage infiltration, apoptosis, interstitial fibrosis, impaired systolic function, and marked increases in ceramide and DAG contents, while no such pathological alterations were observed in AKO+cHSL tissues. Furthermore, electron microscopy revealed considerable LDs, damaged mitochondria, and disrupted intercalated discs in AKO cardiomyocytes, none of which were noted in AKO+cHSL cardiomyocytes. Importantly, the lifespan of AKO+cHSL mice was comparable to that of Wt mice. We conclude cardiac HSL overexpression normalizes lipotoxic cardiomyopathy in AKO mice. These findings highlight the applicability of cardiac HSL activation as a therapeutic strategy for ATGL deficiency-associated lipotoxic cardiomyopathies.
View details for DOI 10.1016/j.jlr.2022.100194
View details for PubMedID 35283217