Angiotensin-converting enzyme 2 regulates endoplasmic reticulum stress and mitochondrial function to preserve skeletal muscle lipid metabolism
Angiotensin-converting enzyme 2 regulates endoplasmic reticulum stress and mitochondrial function to preserve skeletal muscle lipid metabolism
复制标题
血管紧张素转换酶 2 调节内质网应激和线粒体功能以保护骨骼肌脂质代谢
DOI：
10.1186/s12944-019-1145-x
复制
发表时间：
2019-11-27
影响因子：
4.5
通讯作者：
Xin, Zhong
中科院分区：
文献类型：
--
作者：
Cao, Xi;Lu, Xin-Meng;Xin, Zhong
内质网应激和线粒体功能影响肌内脂肪积累。然而，血管紧张素转换酶2（ACE 2）对内质网应激和线粒体功能的调节在预防肌内脂肪代谢中的作用尚不清楚。方法采用酶联免疫吸附法（ELISA）检测ACE 2基因敲除小鼠和Ad-ACE 2处理db/db小鼠骨骼肌中甘油三酯（TG）含量，并分析ACE 2对骨骼肌内质网应激和线粒体脂质代谢功能的影响。RT-PCR检测脂肪生成相关基因ACCα、SREBP-1c、LXRα、CPT-1α、PGC-1α和PPAR α、内质网应激相关基因GRP 78、eIF 2 α、ATF 4、BCL-2和SDH 6的表达。RT-PCR检测ACE 2过表达C2 C12细胞脂质代谢、内质网应激及线粒体功能相关基因。结果ACE 2基因敲除小鼠骨骼肌组织中脂质沉积增加，IKKβ/NFκB/IRS-1信号通路的表达增强。ACE 2基因敲除小鼠表现出骨骼肌中ER应激水平升高和线粒体功能障碍。相反，ACE 2的激活可以改善ER应激和线粒体功能，这轻微地伴随着降低TG含量和下调骨骼肌脂肪生成蛋白的表达在db/db小鼠中。此外，ACE 2改善骨骼肌脂质代谢和C2 C12细胞中的ER应激基因。结论ACE 2可能通过改善内质网和线粒体功能，在肌内脂肪调节中发挥重要作用。本研究可能为治疗骨骼肌胰岛素抵抗提供一种策略。
ObjectiveEndoplasmic reticulum (ER) stress and mitochondrial function affected intramuscular fat accumulation. However, there is no clear evident on the effect of the regulation of ER stress and mitochondrial function by Angiotensin-converting enzyme 2 (ACE2) on the prevention of intramuscular fat metabolism. We investigated the effects of ACE2 on ER stress and mitochondrial function in skeletal muscle lipid metabolism.MethodsThe triglyceride (TG) content in skeletal muscle of ACE2 knockout mice and Ad-ACE2-treated db/db mice were detected by assay kits. Meanwhile, the expression of lipogenic genes (ACCα,SREBP-1c,LXRα,CPT-1α, PGC-1αandPPARα), ER stress and mitochondrial function related genes (GRP78,eIF2α,ATF4,BCL-2, andSDH6) were analyzed by RT-PCR. Lipid metabolism, ER stress and mitochondrial function related genes were analyzed by RT-PCR in ACE2-overexpression C2C12 cell. Moreover, the IKKβ/NFκB/IRS-1 pathway was determined using lysate sample from skeletal muscle of ACE2 knockout mice.ResultsACE2 deficiency in vivo is associated with increased lipid accumulation in skeletal muscle. The ACE2 knockout mice displayed an elevated level of ER stress and mitochondrial dysfunctions in skeletal muscle. In contrast, activation of ACE2 can ameliorate ER stress and mitochondrial function, which slightly accompanied by reduced TG content and down-regulated the expression of skeletal muscle lipogenic proteins in the db/db mice. Additionally, ACE2 improved skeletal muscle lipid metabolism and ER stress genes in the C2C12 cells. Mechanistically, endogenousACE2improved lipid metabolism through the IKKβ/NFκB/IRS-1 pathway in skeletal muscle.ConclusionsACE2 was first reported to play a notable role on intramuscular fat regulation by improving endoplasmic reticulum and mitochondrial function. This study may provide a strategy for treating insulin resistance in skeletal muscle.