Exogenous H(2) S promotes ubiquitin-mediated degradation of SREBP1 to alleviate diabetic cardiomyopathy via SYVN1 S-sulfhydration.
Exogenous H(2) S promotes ubiquitin-mediated degradation of SREBP1 to alleviate diabetic cardiomyopathy via SYVN1 S-sulfhydration.
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DOI：
10.1002/jcsm.13347
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发表时间：
2023-12
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中科院分区：
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糖尿病性心肌病是糖尿病的一种独特的并发症，与细胞内脂质沉积有关。然而，控制心肌细胞内脂滴异常积聚的复杂分子机制仍有待全面阐明。采用200 μmol/L棕榈酸酯和200 μmol/L油酸酯处理的肥胖糖尿病（db/db）小鼠和HL‐1细胞模拟2型糖尿病。采用透射电镜观察小鼠心脏内脂滴的大小和数量。转录组学分析用于询问mRNA水平。脂质组学和泛素组学研究了小鼠脂质组成的改变和参与泛素介导降解的蛋白质。临床数据来自糖尿病相关心肌病患者和健康对照者。Western blot分析评估与脂质代谢相关的蛋白质水平，生物素转换测定用于定量蛋白质半胱氨酸S -巯基化水平。H2S供体NaHS有效地恢复了db/db小鼠心脏组织和血浆中的硫化氢水平（+7%,P < 0.001; +5%, P < 0.001）。db/db小鼠（+210%,P < 0.001）和糖尿病患者（+83%,P = 0.22, n = 5）均表现出血浆甘油三酯水平升高。GYY4137治疗可有效降低db/db小鼠的甘油三酯水平（- 43%,P = 0.007）。与野生型小鼠（胱硫氨酸γ -裂解酶：- 31%，P = 0.0240; SYVN1: - 35%, P = 0.01）和NaHS处理小鼠（SYVN1: - 31%, P = 0.03）相比，db/db小鼠的胱硫氨酸γ -裂解酶和HMG - CoA还原酶降解蛋白1 （SYVN1: - 31%, P = 0.03）的表达降低。相反，与对照组和NaHS处理小鼠相比，甾醇调节元件结合蛋白1 （SREBP1）的表达升高（分别为+91%，P = 0.007; +51%, P = 0.03），二酰基甘油O‐酰基转移酶1 (DGAT1) （+95%, P = 0.001; +35%, P = 0.02）和1‐酰基甘油- 3‐磷酸O‐酰基转移酶3 (AGPAT3) （+88%, P = 0.01; +22%, P = 0.32）的表达也升高。外源H2S导致脂滴形成减少（- 48%,P < 0.001）， SYVN1表达恢复，SYVN1 S -巯基化状态改变，SREBP1泛素化增强。Cys115位点突变的SYVN1过表达降低SREBP1泛素化，增加脂滴数量。外源性H2S通过调节SYVN1的半胱氨酸S -巯基化，增强SREBP1的泛素蛋白酶体降解，减少其核易位。这一途径限制了心肌细胞中的脂滴积聚，改善了糖尿病性心肌病。
Diabetic cardiomyopathy, a distinctive complication of diabetes mellitus, has been correlated with the presence of intracellular lipid deposits. However, the intricate molecular mechanisms governing the aberrant accumulation of lipid droplets within cardiomyocytes remain to be comprehensively elucidated. Both obese diabetic (db/db) mice and HL‐1 cells treated with 200 μmol/L palmitate and 200 μmol/L oleate were used to simulate type 2 diabetes conditions. Transmission electron microscopy is employed to assess the size and quantity of lipid droplets in the mouse hearts. Transcriptomics analysis was utilized to interrogate mRNA levels. Lipidomics and ubiquitinomics were employed to explore the lipid composition alterations and proteins participating in ubiquitin‐mediated degradation in mice. Clinical data were collected from patients with diabetes‐associated cardiomyopathy and healthy controls. Western blot analysis was conducted to assess the levels of proteins linked to lipid metabolism, and the biotin‐switch assay was employed to quantify protein cysteine S‐sulfhydration levels. The administration of H2S donor, NaHS, effectively restored hydrogen sulfide levels in both the cardiac tissue and plasma of db/db mice (+7%, P < 0.001; +5%, P < 0.001). Both db/db mice (+210%, P < 0.001) and diabetic patients (+83%, P = 0.22, n = 5) exhibit elevated plasma triglyceride levels. Treatment with GYY4137 effectively lowers triglyceride levels in db/db mice (−43%, P = 0.007). The expression of cystathionine gamma‐lyase and HMG‐CoA reductase degradation protein 1 (SYVN1) was decreased in db/db mice compared with the wild‐type mice (cystathionine gamma‐lyase: −31%, P = 0.0240; SYVN1: −35%, P = 0.01), and NaHS‐treated mice (SYVN1: −31%, P = 0.03). Conversely, the expression of sterol regulatory element‐binding protein 1 (SREBP1) was elevated (+91%, P = 0.007; +51%, P = 0.03 compared with control and NaHS‐treated mice, respectively), along with diacylglycerol O‐acyltransferase 1 (DGAT1) (+95%, P = 0.001; +35%, P = 0.02) and 1‐acylglycerol‐3‐phosphate O‐acyltransferase 3 (AGPAT3) (+88%, P = 0.01; +22%, P = 0.32). Exogenous H2S led to a reduction in lipid droplet formation (−48%, P < 0.001), restoration of SYVN1 expression, modification of SYVN1's S‐sulfhydration status and enhancement of SREBP1 ubiquitination. Overexpression of SYVN1 mutated at Cys115 decreased SREBP1 ubiquitination and increased the number of lipid droplets. Exogenous H2S enhances ubiquitin‐proteasome degradation of SREBP1 and reduces its nuclear translocation by modulating SYVN1's cysteine S‐sulfhydration. This pathway limits lipid droplet buildup in cardiac myocytes, ameliorating diabetic cardiomyopathy.
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影响因子：
6.8
作者：
Mallela SK;Ge M;Molina J;Santos JV;Kim JJ;Mitrofanova A;Al-Ali H;Marples B;Merscher S;Fornoni A
通讯作者：
Fornoni A
影响因子：
4.8
作者：
Sharma, S;Adrogue, JV;Taegtmeyer, H
通讯作者：
Taegtmeyer, H
影响因子：
37.8
作者：
Bibli, Sofia-Iris;Hu, Jiong;Fleming, Ingrid
通讯作者：
Fleming, Ingrid
影响因子：
5.1
作者：
Cho, N. H.;Shaw, J. E.;Malanda, B.
通讯作者：
Malanda, B.
内质网应激在人类病理学中的作用。
DOI：
10.1146/annurev-pathol-012513-104649
发表时间：
2015
期刊：
Annual review of pathology
影响因子：
--
作者：
Oakes SA;Papa FR
通讯作者：
Papa FR