Hydrogen sulfide stimulates activation of hepatic stellate cells through increased cellular bio-energetics

Hepatic fibrosis is caused by chronic inflammation and characterized as the excessive accumulation of extracellular matrix (ECM) by activated hepatic stellate cells (HSCs). Gasotransmitters like NO and CO are known to modulate inflammation and fibrosis, however, little is known about the role of the gasotransmitter hydrogen sulfide (H₂S) in liver fibrogenesis and stellate cell activation. Endogenous H₂S is produced by the enzymes cystathionine β-synthase (CBS), cystathionine γ-lyase (CTH) and 3-mercaptopyruvate sulfur transferase (MPST) [1]. The aim of this study was to elucidate the role of endogenously produced and/or exogenously administered H₂S on rat hepatic stellate cell activation and fibrogenesis. Primary rat HSCs were culture-activated for 7 days and treated with different H₂S releasing donors (slow releasing donor GYY4137, fast releasing donor NaHS) or inhibitors of the H₂S producing enzymes CTH and CBS (DL-PAG, AOAA). The main message of our study is that mRNA and protein expression level of H₂S synthesizing enzymes are low in HSCs compared to hepatocytes and Kupffer cells. However, H₂S promotes hepatic stellate cell activation. This conclusion is based on the fact that production of H₂S and mRNA and protein expression of its producing enzyme CTH are increased during hepatic stellate cell activation. Furthermore, exogenous H₂S increased HSC proliferation while inhibitors of endogenous H₂S production reduce proliferation and fibrotic makers of HSCs. The effect of H₂S on stellate cell activation correlated with increased cellular bioenergetics. Our results indicate that the H₂S generation in hepatic stellate cells is a target for anti-fibrotic intervention and that systemic interventions with H₂S should take into account cell-specific effects of H₂S.