Profile of cardiac lipid metabolism in STZ-induced diabetic mice.
Profile of cardiac lipid metabolism in STZ-induced diabetic mice.
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STZ 诱导的糖尿病小鼠心脏脂质代谢概况
DOI：
10.1186/s12944-018-0872-8
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发表时间：
2018-10-09
影响因子：
4.5
通讯作者：
Jiang L
中科院分区：
文献类型：
--
作者：
Li W;Yao M;Wang R;Shi Y;Hou L;Hou Z;Lian K;Zhang N;Wang Y;Li W;Wang W;Jiang L
脂毒性导致糖尿病性心肌病。在这项研究中，我们研究了导致糖尿病小鼠心脏脂毒性的脂质种类及其与过氧化物酶体β-氧化的关系。将雄性C57 BL/6小鼠随机分为糖尿病组（腹腔注射STZ）和对照组（生理盐水）。通过超声心动图评价心功能指标[射血分数（EF%）和短轴缩短率（FS%）]。苏木精-伊红染色后电镜观察心肌组织和线粒体的形态学变化。用全自动生化分析仪测定心肌损伤指标和血脂。使用市售试剂盒分析心脏ATP水平。采用定量逆转录聚合酶链反应检测葡萄糖转运蛋白4（GLUT 4）、脂肪酸结合蛋白3（FABP 3）、棕榈酰转移酶1α（CPT-1α）、酰基辅酶A氧化酶1（AOX 1）、D-双功能蛋白（DBP）、3-酮脂酰辅酶A硫解酶A（THLA）、解偶联蛋白（UCP）2和UCP 3的mRNA水平。Western blotting分析FABP 3蛋白表达。应用LC-MS/MS非靶向代谢组学技术评价心脏脂质代谢。与对照组相比，糖尿病小鼠的EF%和FS%显著降低。心肌损伤指标、血脂、心肌线粒体嵴融合度均明显增高。在糖尿病心脏中，GLUT 4表达减少，而FABP 3、CPT-1α、AOX 1、DBP、THLA、UCP 2和UCP 3表达增加，ATP水平降低。总的来说，113种脂质在两组之间表现出显著的差异表达（FC > 2，P < 0.05），其中鞘脂代谢被鉴定为受影响的首要经典途径。在糖尿病心脏中，长链羟基-酰基肉毒碱（8/8）和酰基肉毒碱（6/11）、甘油三酯（2/5）和二酰基甘油（3/7）上调，而极长链多不饱和脂肪酸（PUFA）（5/6）包括二十碳五烯酸、二十二碳六烯酸、磷酸胆碱（11/19）、溶血磷酸胆碱（5/9）、磷酸乙醇胺（7/11）、溶血磷脂乙醇胺（7/10）、磷脂酰甘油（6/8）、磷酸丝氨酸（6/8）、磷脂酰肌醇（2/2）、磷脂酸（1/1）、溶血磷脂酸（1/1）和鞘磷脂（6/6）表达下调。我们的数据表明，毒性脂质种类的增加和经历过氧化物酶体β-氧化的PUFA的减少，结合磷脂的减少，导致线粒体损伤和随后的磷酸化解偶联和ATP缺乏;从而导致糖尿病心脏功能障碍。
Lipotoxicity contributes to diabetic myocardial disease. In this study, we investigated the lipid species contributing to lipotoxicity and the relationship with peroxisomal β-oxidation in the heart of diabetic mice. Male C57BL/6 mice were randomly divided into a Diabetic group (intraperitoneal injection of STZ) and a Control group (saline). Cardiac function indexes [ejection fraction (EF%) and fractional shortening (FS%)] were evaluated by echocardiography. Morphological changes in the myocardial tissues and mitochondria were assessed by electron microscopy following hematoxylin and eosin staining. Blood myocardial injury indexes and lipids were measured using an automatic biochemical analyzer. Cardiac ATP levels were analyzed using a commercially available kit. mRNA levels of glucose transporter 4 (GLUT4), fatty acid binding protein 3 (FABP3), palmitoyl transferase 1α (CPT-1α), acyl-CoA oxidase 1 (AOX1), D-bifunctional protein (DBP), 3-ketoacyl-CoA thiolase A (THLA), uncoupling protein (UCP) 2 and UCP3 were investigated by quantitative reverse-transcription polymerase chain reaction. FABP3 protein expression was analyzed by Western blotting. Non-targeted metabolomics by LC-MS/MS was applied to evaluate profile of lipid metabolism in heart. Compared with controls, EF% and FS% were significantly reduced in diabetic mice. Furthermore, blood myocardial injury indexes and lipids, as well as myocardial mitochondrial cristae fusion were significantly increased. In the diabetic heart, GLUT4 expression was decreased, while expression of FABP3, CPT-1α, AOX1, DBP, THLA, UCP2 and UCP3 was increased, and ATP levels were reduced. In total, 113 lipids exhibited significant differential expression (FC > 2, P < 0.05) between the two groups, with sphingolipid metabolism identified as the top-ranking affected canonical pathway. In the diabetic heart, long-chain hydroxyl-acylcarnitines (8/8) and acylcarnitines (6/11), triglycerides (2/5), and diacyglycerol (3/7) were upregulated, while very long-chain polyunsaturated fatty acids (PUFAs) (5/6) including eicosapentaenoate, docosahexaenoate, phosphocholine (11/19), lysophosphocholine (5/9), phosphoethanolamine (7/11), lysophosphoethanolamine (7/10), phosphatidylglycerol (6/8), phosphoserine (6/8), phosphatidylinositol (2/2), phosphatidic acid (1/1), lysophosphatidic acid (1/1) and sphingomyelin (6/6) were downregulated. Our data suggest that the increase in toxic lipid species and decreased in PUFAs undergoing peroxisomal β-oxidation, combined with the reduction in phospholipids cause mitochondrial injury and subsequent uncoupling of phosphorylation and ATP deficiency; thereby leading to diabetic heart dysfunction.
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通讯作者：
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