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Hydrogen sulphide reduced the accumulation of lipid droplets in cardiac tissues of db/db mice via Hrd1 S-sulfhydration.

ABSTRACT: Accumulation of lipid droplets (LDs) induces cardiac dysfunctions in type 2 diabetes patients. Recent studies have shown that hydrogen sulphide (H₂ S) ameliorates cardiac functions in db/db mice, but its regulation on the formation of LDs in cardiac tissues is unclear. Db/db mice were injected with NaHS (40 μmol·kg^-1 ) for twelve weeks. H9c2 cells were treated with high glucose (40 mmol/L), oleate (200 µmol/L), palmitate (200 µmol/L) and NaHS (100 µmol/L) for 48 hours. Plasmids for the overexpression of wild-type Hrd1 and Hrd1 mutated at Cys115 were constructed. The interaction between Hrd1 and DGAT1 and DGAT2, the ubiquitylation level of DGAT1 and 2, the S-sulfhydration of Hrd1 were measured. Exogenous H₂ S ameliorated the cardiac functions, decreased ER stress and reduced the number of LDs in db/db mice. Exogenous H₂ S could elevate the ubiquitination level of DGAT 1 and 2 and increased the expression of Hrd1 in cardiac tissues of db/db mice. The S-sulfhydration of Hrd1 by NaHS enhanced the interaction between Hrd1 and DGAT1 and 2 to inhibit the formation of LD. Our findings suggested that H₂ S modified Hrd1 S-sulfhydration at Cys115 to reduce the accumulation of LDs in cardiac tissues of db/db mice.

SUBMITTER: Sun Y

PROVIDER: S-EPMC8500968 | biostudies-literature | 2021 Oct

REPOSITORIES: biostudies-literature

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Hydrogen sulphide reduced the accumulation of lipid droplets in cardiac tissues of db/db mice via Hrd1 S-sulfhydration.

Sun Yu Y Zhang Linxue L Lu Baoling B Wen Jingchen J Wang Mengyi M Zhang Shiwu S Li Qianzhu Q Shu Feng F Lu Fangping F Liu Ning N Peng Shuo S Zhao Yajun Y Dong Shiyun S Lu Fanghao F Zhang Weihua W Wang Yan Y

Journal of cellular and molecular medicine 20210925 19

Accumulation of lipid droplets (LDs) induces cardiac dysfunctions in type 2 diabetes patients. Recent studies have shown that hydrogen sulphide (H<sub>2</sub> S) ameliorates cardiac functions in db/db mice, but its regulation on the formation of LDs in cardiac tissues is unclear. Db/db mice were injected with NaHS (40 μmol·kg<sup>-1</sup> ) for twelve weeks. H9c2 cells were treated with high glucose (40 mmol/L), oleate (200 µmol/L), palmitate (200 µmol/L) and NaHS (100 µmol/L) for 48 hours. Plas ...[more]

PMID: 34562065

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Project description:Hydrogen sulfide (H2S) plays physiological roles in vascular tone regulation, cytoprotection, and ATP synthesis. HMG-CoA reductase degradation protein (Hrd1), an E3 ubiquitin ligase, is involved in protein trafficking. H2S may play a role in controlling fatty acid uptake in diabetic cardiomyopathy (DCM) in a manner correlated with modulation of Hrd1 S-sulfhydration; however, this role remains to be elucidated. The aim of the present study was to examine whether H2S can attenuate lipid accumulation and to explain the possible mechanisms involved in the regulation of the H2S-Hrd1/VAMP3 pathway. Db/db mice and neonatal rat cardiomyocytes treated with high glucose, palmitate and oleate were used as animal and cellular models of type 2 diabetes, respectively. The expression of cystathionine-γ-lyase (CSE), Hrd1, CD36 and VAMP3 was detected by Western blot analysis. In addition, Hrd1 was mutated at Cys115, and Hrd1 S-sulfhydration was examined using an S-sulfhydration assay. VAMP3 ubiquitylation was investigated by immunoprecipitation. Lipid droplet formation was tested by TEM, BODIPY 493/503 staining and oil red O staining. The expression of CSE and Hrd1 was decreased in db/db mice compared to control mice, whereas CD36 and VAMP3 expression was increased. NaHS administration reduced droplet formation, and exogenous H2S restored Hrd1 expression, modified S-sulfhydration, and decreased VAMP3 expression in the plasma membrane. Using LC-MS/MS analysis, we identified 85 proteins with decreased ubiquitylation, including 3 vesicle-associated membrane proteins, in the cardiac tissues of model db/db mice compared with NaHS-treated db/db mice. Overexpression of Hrd1 mutated at Cys115 diminished VAMP3 ubiquitylation, whereas it increased CD36 and VAMP3 expression and droplet formation. siRNA-mediated Hrd1 deletion increased the expression of CD36 in the cell membrane. These findings suggested that H2S regulates VAMP3 ubiquitylation via Hrd1 S-sulfhydration at Cys115 to prevent CD36 translocation in diabetes.

Dataset Information

Hydrogen sulphide reduced the accumulation of lipid droplets in cardiac tissues of db/db mice via Hrd1 S-sulfhydration.

Publications

Hydrogen sulphide reduced the accumulation of lipid droplets in cardiac tissues of db/db mice via Hrd1 S-sulfhydration.

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