期刊
JOURNAL OF LIPID RESEARCH
卷 63, 期 5, 页码 -出版社
ELSEVIER
DOI: 10.1016/j.jlr.2022.100194
关键词
Supplementary key words apoptosis; beta-oxidation; ceramides; FA; lipid droplets; lipotoxicity; macrophage; mitochondria; perilipins; triacylglycerol
资金
- University of Fukui
- Ministry of Education, Culture, Sports, Science and Technology in Japan [26461360]
- National Institute of Diabetes and Digestive and Kidney Diseases [P30 DK-116074]
- Grants-in-Aid for Scientific Research [26461360] Funding Source: KAKEN
This study demonstrates that overexpression of HSL can restore lipotoxicity in the hearts of ATGL-deficient mice, normalizing cardiac function and structure. These findings highlight the potential of cardiac HSL activation as an effective strategy for treating lipotoxic cardiomyopathy associated with ATGL deficiency.
Lipid droplets (LDs) are multifunctional organelles that regulate energy storage and cellular homeostasis. The first step of triacylglycerol 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 lipase in the heart, we hypothesized that activation of HSL might compensate for ATGL deficiency. To test this hypothesis, we crossed ATGL-KO (AKO) mice and cardiac-specific HSL-overexpressing mice (cHSL) to establish homozygous AKO mice and AKO mice with cardiac specific HSL overexpression (AKO+cHSL). We found that cardiac triacylglycerol content was 160 fold higher in AKO relative to Wt mice, whereas that of AKO+cHSL mice was comparable to the latter. In addition, AKO cardiac tissues exhibited reduced mRNA expression of PPAR alpha-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 diacylglycerol contents, whereas 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 life span of AKO+cHSL mice was comparable to that of Wt mice. HSL over expression normalizes lipotoxic cardiomyopathy in AKO mice and the findings highlight the applicability of cardiac HSL activation as a therapeutic strategy for ATGL deficiency-associated lipotoxic cardiomyopathies.
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