The Liver as a Central Regulator of Hydrogen Sulfide

Abstract

The liver is likely exposed to high levels of H2S from endogenous hepatic synthesis and exogenous sources from the gastrointestinal tract. Little is known about the consequence of H2S exposure on the liver or hepatic regulation of H2S levels. We hypothesized that the liver has a high capacity to metabolize H2S and that H2S oxidation is decreased during sepsis; a condition in which hepatic O2 is limited and H2S synthesis is increased. Using a non-recirculating isolated and perfused liver system, we demonstrated rapid hepatic H2S metabolism up to an infusion concentration 200μM H2S. H2S metabolism was associated with an increase in O2 consumption from a baseline 96.7 ± 7.6 μmoles O2/min/kg to 109 ± 7.4 μmoles O2/min/kg at an infusion concentration of 150 μM H2S (P<0.001). Removal of O2 from the perfusate decreased H2S clearance from a maximal 97% to only 23%. Livers isolated from rats subjected to cecal ligation and puncture (CLP) did not differ significantly from control livers in their capacity to metabolize H2S suggesting that H2S oxidation remains a priority during sepsis. To test whether H2S induces O2 consumption in vivo, intravital microscopy was utilized to monitor the oxygen content in the hepatic microenvironment. Infusion of H2S increased the NADH/NAD+ ratio (645 grey scale unit increase, P=0.035) and decreased hepatic O2 availability visualized with Ru(Phen)32+ (439 grey scale unit increase, P=0.040). We conclude that the liver has a high hepatic capacity for H2S metabolism. Moreover, H2S oxidation consumes available oxygen and may exacerbate the tissue hypoxia associated with sepsis.

Decreased Cystathionine-γ-lyase (CSE) Activity in Livers of Type 1 Diabetic Rats and Peripheral Blood Mononuclear Cells (PBMC) of Type 1 Diabetic Patients

“…Several experimental studies have demonstrated that CSE is a major participant in the maintenance of cardiovascular function (7, 14 -16). Liver is the central regulator of endogenous H 2 S production (29). Recent studies demonstrated that in liver the abundance of CSE is 60-fold higher than that of CBS, and their results showed that although CSE accounts for 97-99% of the hepatic H 2 S output, CBS accounts for only 3% of hepatic H 2 S generation capacity (61).…”

“…Results from both cell culture and animal studies suggest that lower H 2 S levels may play a role in the pathogenesis of diabetic complications (5, 13, 22, 26 -28). Liver is the major tissue responsible for the production of H 2 S (29). Although Moore and co-workers (23) reported an increase in mRNA expression of both CSE and CBS in the liver tissue of * This work was supported, in whole or in part, by a National Institutes of STZ-induced T1D rats, Szabo and co-workers (22) did not find any significant changes in the protein expression of CSE or CBS in the liver tissue of STZ-diabetic rats.…”

A Practical Look at the Chemistry and Biology of Hydrogen Sulfide

“…Fifth, H 2 S is rapidly removed from the circulation by tissues. Norris et al (51) have shown that the buffer-perfused rat liver removes nearly 97% H 2 S at a perfusate concentration of 150 lM H 2 S and 50% clearance at 300 lM H 2 S. Sixth, H 2 S has been shown to be rapidly consumed by tissues in the presence of oxygen (Fig. 6A) (35,56,57).…”

Hydrogen Sulfide Attenuates Inflammatory Hepcidin by Reducing IL-6 Secretion and Promoting SIRT1-Mediated STAT3 Deacetylation

“…Biosynthesis of H 2 S has been identified in a variety of mammalian tissues. In the liver, H 2 S is endogenously produced by cystathionine b-synthase (CBS) and cystathionine c-lyase (CSE) with l-cysteine as the substrate, in addition to 3-mercaptopyruvate sulfur transferase with 3-mercaptopyruvate (33,38,50). Previous studies revealed that H 2 S plays a prominent role in inflammatory responses (22,36).…”