心肌脂滴堆积是II型糖尿病心肌病发生的主要特点，降低心脏功能，但机制尚不清楚。我们发现，db/db小鼠心肌脂滴数量随病程的延长而增加，而H2S含量明显降低；给予外源性H2S减少db/db小鼠心肌脂滴数量和脂肪酸浓度，改善心脏功能；H2S上调泛素化E3连接酶羟甲基戊二酸还原酶降解蛋白（Hrd1）的巯基硫化修饰；LC-MS结果证实，外源性H2S增加脂滴形成关键蛋白二酰甘油酰基转移酶（DGAT）泛素化水平。我们推测“气体分子H2S通过对Hrd1S-巯基硫化修饰，增加脂滴形成关键酶DGAT泛素化水平影响脂滴形成，同时调控脂肪酸在线粒体的代谢；以及细胞核内脂肪酸对Sirt6活性和组蛋白乙酰化的影响，促进代谢编程重排，启动糖尿病心肌的保护作用”。本研究明确H2S修饰Hrd1S-巯基硫化的位点，调控其底物的泛素化水平，影响心肌脂滴及脂肪酸在内质网、线粒体和细胞核的代谢，揭示H2S保护糖尿病心肌的新机制。

Accumulation of lipid droplet is one of the main characters in diabetic cardiomyopathy, which decreases the cardiac function. However, its mechanism is unclear. Our previous results demonstrated that exogenous H2S decreased the number and the size of lipid droplets and the concentration of fatty acid to ameliorate cardiac functions. More evidence demonstrates that gaseous H2S modifies S-Sulfhydration of target proteins to regulate the activities of them. Our data revealed that H2S upregulated the level of S-Sulfhydration of E3 ligase hydroxymethyl glutaryl reductase degradation protein1(Hrd1), LC-MS results demonstrated that exogenous H2S increased the ubiquitylation level of DGAT, which is one of the key enzymes of lipid droplet formation. Therefore, we postulate that gaseous H2S modifies S-Sulfhydration of E3 ligase Hrd1 to regulate the ubiquitylation of DAGT, and lipid droplet formation and fatty acid metabolism in mitochondria. Fatty acid also regulates the activity of Sirt6 in nucleus, which effects on acetylation of histone to promote metabolism reprogram. Db/db mice and rat newborn cardiomyocytes, as animal and cell model, are used in this study. This study explains that H2S modifies the sites of S-Sulfhydration of Hrd1 and regulates the ubiquitin of DGAT to reveal the lipid metabolism in cardiac tissues. Above results demonstrates that H2S protects against diabetic cardiomyopathy.