Liver X Receptor Activation Alleviates Hepatic Ischemia-Reperfusion Injury in Diabetes by Inhibiting NF-κB-NLRP3 Activation

Introduction: Hyperglycemia has been reported to be a crucial factor that aggravates liver ischemia-reperfusion injury (IRI). Macrophage-mediated inflammatory injury is vital to liver IRI. A positive effect of Liver X receptor (LXR) on diabetes has been proven; however, the function and mechanism of LXR in diabetic liver IRI remain unclear. Accordingly, our study concentrates on the mechanism underly.

Materials and methods: Streptozotocin (STZ, 40 mg/kg)-treated diabetic mice were used to establish a liver IRI model. Bone marrow-derived macrophages (BMDMs) were used in studying the role of macrophage inflammation in diabetic liver. GW3965 hydrochloride was used to activate LXR in vivo and in vitro. QD394, a lipid peroxidation agonist, was used to verify the underlying mechanism.

Results: Hyperglycemia exacerbates liver ischemia-reperfusion injury (IRI) by promoting hepatic cell death and inflammation in vivo. In diabetic livers, the expression of liver X receptors (LXRs) is significantly reduced. Furthermore, the ischemia-reperfusion process itself further decreases LXR levels. Application of the LXR Agonist GW3965 mitigates macrophage lipid peroxidation and inflammasome NLRP3 (NOD-like Receptor thermal protein domain associated protein 3) inflammasome activation in vitro, thereby protecting the liver from severe IRI. The results were further confirmed by the rescue experiments.

Conclusions: LXRs play an important role in diabetic liver IRI and macrophage-associated inflammation. Pharmacologic activation of LXRs alleviates macrophage inflammatory activation in diabetic liver IRI, and may serve as a potential therapeutic target for diabetes-related liver injury.

LXR; diabetes; liver ischemia‐reperfusion injury; macrophage.