Hydrogen Sulfide Alleviates Liver Injury Through the S‐Sulfhydrated‐Kelch‐Like ECH‐Associated Protein 1/Nuclear Erythroid 2–Related Factor 2/Low‐Density Lipoprotein Receptor–Related Protein 1 Pathway

Abstract

Background and Aims Protein S‐sulfhydration mediated by H2S has been shown to play important roles in several diseases. However, its precise role in liver disease and the related mechanism remain unclear. Approach and Results We showed that in streptozotocin (STZ)–treated and high‐fat diet (HFD)–treated low‐density lipoprotein receptor–negative (LDLr−/−) mice, the H2S donor GYY4137 ameliorated liver injury, decreased serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels, mitigated lipid deposition, and reduced hepatocyte death. Strikingly, S‐sulfhydration of Kelch‐like ECH‐associated protein 1 (Keap1) was decreased in the livers of patients with fatty liver under diabetic conditions. In STZ+HFD‐treated LDLr−/− mice and in high glucose–treated and oxidized low‐density lipoprotein (ox‐LDL)–treated primary mouse hepatocytes, the GYY4137‐mediated increase in Keap1 S‐sulfhydration induced nuclear erythroid 2‐related factor 2 (Nrf2) dissociation from Keap1, which enhanced the nuclear translocation of Nrf2 itself and the consequent expression of antioxidant proteins. Keap1 Cys151 mutation significantly reduced Keap1 S‐sulfhydration and abolished the hepatoprotective effects of H2S both in vivo and in vitro. Nrf2 deficiency inhibited the H2S‐induced beneficial impacts in Nrf2−/− mice. Similarly, in CCl4‐stimulated mice, GYY4137 increased Keap1 S‐sulfhydration, improved liver function, alleviated liver fibrosis, decreased hepatic oxidative stress, and activated the Nrf2 signaling pathway; and these effects were abrogated after Keap1 Cys151 mutation. Moreover, H2S increased the binding of Nrf2 to the promoter region of LDLr‐related protein 1 (Lrp1) and consequently up‐regulated LRP1 expression, but these effects were disrupted by Keap1 Cys151 mutation. Conclusions H2S‐mediated Keap1 S‐sulfhydration alleviates liver damage through activation of Nrf2. Hence, administration of exogenous H2S in the form of the H2S donor GYY4137 may be of therapeutic benefit in the context of concurrent hyperlipidemia and hyperglycemia–induced or CCl4‐stimulated liver dysfunction.

Hydrogen Sulfide Is a Regulator of Hemoglobin Oxygen‐Carrying Capacity via Controlling 2,3‐BPG Production in Erythrocytes

“…The level of H 2 S in plasma was measured following the method described by prior studies [ 26 , 27 ]. Briefly, a volume of 40 μ l plasma was mixed with 62.5 μ l Zn acetate (1%, w / v ) and 100 μ l distilled water.…”

Nutraceutical Strategies for Suppressing NLRP3 Inflammasome Activation: Pertinence to the Management of COVID-19 and Beyond

“…Physiological concentrations of the endogenously generated gas hydrogen sulfide (H 2 S) have been found to inhibit inflammasome activity in preclinical studies [ 182 , 183 , 184 , 185 ]. This may reflect, at least in part, its ability to act both as a phase 2 inducer, and as an activator of AMPK [ 186 , 187 , 188 , 189 , 190 ]. The latter effect is contingent on boosted activity of calmodulin-dependent kinase kinase-β, which confers an activating phosphorylation on AMPK [ 191 , 192 , 193 ].…”

<p>Hydrogen Sulfide, Adipose Tissue and Diabetes Mellitus</p>

“…In most studies on H 2 S, inorganic sulfide salts such as sodium hydrosulfide (NaHS) and sodium sulfide (Na 2 S) were used, as they increase the H 2 S concentration rapidly and in the short term. 108 NaHS may activate K + ATP channels, protein kinase B/Akt or Nrf2-induced signalling 109 to exert its protective effects. To overcome the limitations of sulfide salts, several organic, slow-releasing H 2 S compounds have been synthesized, with GYY4137 being the most popular; however, they may possess H 2 S-independent activities mediated by the parent compound.…”