HSPA12A attenuates lipopolysaccharide-induced liver injury through inhibiting caspase-11-mediated hepatocyte pyroptosis via PGC-1α-dependent acyloxyacyl hydrolase expression.

Liver dysfunction is strongly associated with poor survival of sepsis patients. Cytosolic lipopolysaccharide (LPS) sensing by Caspase-4/5/11 for pyroptosis activation is a major driver of the development of sepsis. Studies in macrophages and endothelial cells have demonstrated that LPS is inactivated by acyloxyacyl hydrolase (AOAH) and leading to desensitizing Caspase-4/5/11 to LPS. However, little is known about the cytosolic LPS-induced pyroptosis in hepatocytes during sepsis. Heat shock protein 12A is a novel member of the HSP70 family. Here, we report that LPS increased nuclear translocation in hepatocytes, while knockout of Hduanyu184212A (Hspa12a^-/-) in mice promoted LPS-induced acute liver injury. We also noticed that the LPS-induced Caspase-11 activation and its cleavage of gasdermin D (GSDMD) to produce the membrane pore-forming GSDMD^Nterm (markers of pyroptosis) were greater in livers of Hspa12a^-/- mice compared with its wild type controls. Loss- and gain-of-function studies showed that Hduanyu184212A deficiency promoted, whereas Hduanyu184212A overexpression inhibited, cytosolic LPS accumulation, Caspase-11 activation and GSDMD^Nterm generation in primary hepatocytes following LPS incubation. Notably, LPS-induced AOAH expression was suppressed by Hduanyu184212A deficiency, whereas AOAH overexpression reversed the Hduanyu184212A deficiency-induced promotion of LPS-evoked and Caspase-11-mediated pyroptosis of hepatocytes. In-depth molecular analysis showed that Hduanyu184212A interacted directly with peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α) and increased its nuclear translocation, thereby inducing AOAH expression for cytosolic LPS inactivation, which ultimately leading to inhibition of the Caspase-11 mediated pyroptosis of hepatocytes. Taken together, these findings revealed Hduanyu184212A as a novel player against LPS-induced liver injury by inhibiting cytosolic LPS-induced hepatocyte pyroptosis via PGC-1α-mediated AOAH expression. Therefore, targeting hepatocyte Hduanyu184212A represents a viable strategy for the management of liver injury in sepsis patients.

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