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 (HS) in liver fibrogenesis and stellate cell activation. Endogenous HS 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 HS on rat hepatic stellate cell activation and fibrogenesis. Primary rat HSCs were culture-activated for 7 days and treated with different HS releasing donors (slow releasing donor GYY4137， fast releasing donor NaHS) or inhibitors of the HS producing enzymes CTH and CBS (DL-PAG， AOAA). The main message of our study is that mRNA and protein expression level of HS synthesizing enzymes are low in HSCs compared to hepatocytes and Kupffer cells. However， HS promotes hepatic stellate cell activation. This conclusion is based on the fact that production of HS and mRNA and protein expression of its producing enzyme CTH are increased during hepatic stellate cell activation. Furthermore， exogenous HS increased HSC proliferation while inhibitors of endogenous HS production reduce proliferation and fibrotic makers of HSCs. The effect of HS on stellate cell activation correlated with increased cellular bioenergetics. Our results indicate that the HS generation in hepatic stellate cells is a target for anti-fibrotic intervention and that systemic interventions with HS should take into account cell-specific effects of HS.