Insufficient S-sulfhydration of serum and glucocorticoid-regulated kinase 1 participates in hyperhomocysteinemia-induced liver injury

Background & aims

Previous studies have established that hyperhomocysteinemia (HHcy) significantly contributes to the development of non-alcoholic steatohepatitis (NASH). Conversely, hydrogen sulfide (H₂S) has shown potential in mitigating NASH. Despite these findings, it remains uncertain whether H₂S can serve as a therapeutic agent against HHcy-induced liver damage.

Methods

Mice were fed a high-methionine diet to induce HHcy and HepG2 cells were exposed to homocysteine (Hcy). In both models, we assessed liver injury, H₂S concentration, and autophagy levels. For rescue, sodium hydrosulfide (NaHS), an H₂S donor, was used to test its potential in reversing hepatic pathological features induced by HHcy.

Results

1) Hcy accumulation led to liver damage and increased autophagy. This was linked to insufficient S-sulfhydration of serum and glucocorticoid-regulated kinase 1 (SGK1) at Cys244 and Cys282, a crucial autophagy regulator. The deficiency in S-sulfhydration was resulted from downregulation of cystathionine-γ-lyase (CSE) and subsequent H₂S decrease, leading to SGK1 inactivation. 2) Administration of NaHS reduced the liver damage caused by high Hcy levels and restored H₂S levels, promoting the S-sulfhydration and activation of SGK1. 3) Pharmacological inhibition of SGK1 induced autosis, a specific type of cell death caused by overactivation of autophagy. Conversely, a constitutively active mutant of SGK1 (SGK1^S422D) significantly decreased autophagy and improved cell viability.

Conclusions

NaHS supplementation mitigates HHcy-induced liver injury by downregulating hepatic autophagy through the S-sulfhydration and activation of SGK1. This post-translational modification by H₂S holds promise as a therapeutic approach for HHcy-induced liver injury.