Exogenous hydrogen sulfide improves non-alcoholic fatty liver disease by inhibiting endoplasmic reticulum stress/NLRP3 inflammasome pathway.

Non-alcoholic fatty liver disease (NAFLD) is a common chronic liver disease worldwide, and its exact pathogenesis has not been fully studied. Hydrogen sulfide (HS) is the third gas signaling molecule discovered in mammals, following nitric oxide and carbon monoxide. It has the effects of anti-inflammation, anti-apoptosis, and so on, thereby playing an important role in many diseases. However, the role and mechanism of exogenous HS in NAFLD are not fully understood. In this study, we constructed in vitro and in vivo NAFLD models by feeding mice a high-fat diet and stimulating hepatocytes with palmitic acid, respectively, to investigate the improvement effect and mechanism of exogenous HS on NAFLD. The results showed that NaHS (a donor of HS) treatment alleviated lipid accumulation, inflammation, apoptosis and pyroptosis, and downregulated endoplasmic reticulum (ER) stress and nucleotide-binding oligomerization domain-like receptor containing pyrin domain 3 (NRRP3) inflammasome in NAFLD. The activation of NLRP3 inflammasome weakened NaHS improvement of NAFLD, indicating that exogenous HS ameliorated NAFLD by inhibiting NLRP3 inflammasome-mediated lipid synthesis, inflammation, apoptosis and pyroptosis. Similarly, the activation of ER stress weakened NaHS improvement of NAFLD and NaHS inhibition of NLRP3 inflammasome, indicating that exogenous HS suppressed NLRP3 inflammasome by downregulating ER stress, thus improving NAFLD. Additionally, the protein expressions of NLRP3 and cleaved caspase-1 were downregulated after inhibiting the reactive oxygen species (ROS)/extracellular signal-regulated kinases (ERK) and ROS/thioredoxin-interacting protein (TXNIP) pathways, indicating that ER stress activated NLRP3 inflammasome through the ROS/ERK and ROS/TXNIP pathways. In conclusion, our results indicated that exogenous HS inhibited NLRP3 inflammasome-mediated hepatocytes inflammation, lipid synthesis, apoptosis and pyroptosis by downregulating ER stress, thereby improving NAFLD; Furthermore, ER stress activated NLRP3 inflammasome through the ROS/ERK and ROS/TXNIP pathways in NAFLD. ER stress/NLRP3 inflammasome is expected to become a new target of HS for treating NAFLD.