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.

Keywords: DGAT; Hrd1; Lipid droplets; S-sulfhydration; diabetic cardiomyopathy; hydrogen sulphide.