Exogenous H2S promotes ubiquitin‐mediated degradation of SREBP1 to alleviate diabetic cardiomyopathy via SYVN1 S‐sulfhydration

Abstract

AbstractBackgroundDiabetic 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.MethodsBoth 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.ResultsThe 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.ConclusionsExogenous 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.