Hormone-sensitive lipase protects adipose triglyceride lipase-deficient mice from lethal lipotoxic cardiomyopathy.
Hormone-sensitive lipase protects adipose triglyceride lipase-deficient mice from lethal lipotoxic cardiomyopathy.
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DOI：
10.1016/j.jlr.2022.100194
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发表时间：
2022-05
影响因子：
6.5
通讯作者：
Ishizuka, Tamotsu
中科院分区：
文献类型：
--
作者：
Yamada, Mika;Suzuki, Jinya;Sato, Satsuki;Zenimaru, Yasuo;Saito, Rie;Konoshita, Tadashi;Kraemer, Fredric B.;Ishizuka, Tamotsu
关键词：
脂滴是一种多功能的细胞器，调节能量储存和细胞内稳态。脂肪甘油三酯脂肪酶（ATGL）催化LDs中三酰甘油水解的第一步，缺乏ATGL会导致致死性心脏脂肪变性。虽然脂肪敏感脂肪酶（HSL）的功能作为一个二酰基甘油脂肪酶在心脏中，我们假设，激活HSL可能会弥补ATGL的不足。为了验证这一假设，我们将ATGL-KO（AKO）小鼠和心脏特异性HSL过表达小鼠（cHSL）杂交，以建立纯合子AKO小鼠和心脏特异性HSL过表达的AKO小鼠（AKO+cHSL）。我们发现，心脏三酰甘油含量是160倍高AKO相对于野生型小鼠，而AKO+cHSL小鼠与后者相当。此外，AKO心脏组织表现出PPARα调节基因的mRNA表达降低，以及炎症、纤维化和心脏应激相关基因的上调。相比之下，AKO+cHSL心脏组织表现出的表达水平与Wt小鼠中观察到的相似。AKO心肌组织还表现出巨噬细胞浸润、细胞凋亡、间质纤维化、收缩功能受损以及神经酰胺和甘油二酯含量显著增加，而在AKO+cHSL组织中未观察到此类病理改变。此外，电子显微镜显示AKO心肌细胞中存在大量LD、线粒体受损和闰盘破坏，而AKO+cHSL心肌细胞中未观察到这些情况。重要的是，AKO+cHSL小鼠的寿命与Wt小鼠相当。HSL过表达使AKO小鼠的脂毒性心肌病正常化，并且该发现强调了心脏HSL激活作为ATGL缺乏相关脂毒性心肌病的治疗策略的适用性。
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 PPARα-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 overexpression 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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影响因子：
6.5
作者：
Fortier, M;Soni, K;Mitchell, GA
通讯作者：
Mitchell, GA
影响因子：
56.9
作者：
Haemmerle, G;Lass, A;Zechner, R
通讯作者：
Zechner, R
DOI：
10.1016/j.xcrm.2020.100001
发表时间：
2020-04-21
期刊：
Cell reports. Medicine
影响因子：
--
作者：
Kintscher U;Foryst-Ludwig A;Haemmerle G;Zechner R
通讯作者：
Zechner R
DOI：
10.1016/j.bbalip.2009.04.002
发表时间：
2009-06
影响因子：
4.8
作者：
Bickel, Perry E.;Tansey, John T.;Welte, Michael A.
通讯作者：
Welte, Michael A.
影响因子：
8
作者：
Kong, Ping;Christia, Panagiota;Frangogiannis, Nikolaos G.
通讯作者：
Frangogiannis, Nikolaos G.