Nonalcoholic steatohepatitis (NASH) is the most prevalent cause of chronic liver disease worldwide. Macrophagemediated inflammation plays a critical role in NASH pathogenesis; however, optimum therapies for macrophage activation and NASH remain elusive. HSPA12A encodes a novel member of the HSP70 family. Here, we report that NASH patients showed increased hepatic HSPA12A expression and serum HSPA12A contents. Intriguingly, knockout of HSPA12A (Hspa12a 2/2) in mice attenuated high-fat diet (HFD)-induced hepatic steatosis and injury. HFD-induced macrophage polarization toward an M1 phenotype and inflammatory responses in the liver of Hspa12a 2/2 mice were also attenuated. Loss-and gain-of-function studies revealed that the de novo lipogenesis in hepatocytes was regulated by the paracrine effects of macrophage HSPA12A rather than by hepatocyte HSPA12A. In-depth molecular analysis revealed that HSPA12A interacted with the M2 isoform of pyruvate kinase (PKM2) in macrophages and increased its nuclear translocation, thereby promoting M1 polarization and secretion of proinflammatory M1 cytokines; this led, ultimately, to hepatocyte steatosis via paracrine effects. Taken together, these findings show that HSPA12A acts as a novel regulator of M1 macrophage polarization and NASH pathogenesis by increasing nuclear PKM2. Strategies that inhibit macrophage HSPA12A might be a potential therapeutic intervention for NASH.
Active mechanical metamaterials (AMMs) (or smart mechanical metamaterials) that combine the configurations of mechanical metamaterials and the active control of stimuli-responsive materials have been widely investigated in recent decades. The elaborate artificial microstructures of mechanical metamaterials and the stimulus response characteristics of smart materials both contribute to AMMs, making them achieve excellent properties beyond the conventional metamaterials. The micro and macro structures of the AMMs are designed based on structural construction principles such as, phase transition, strain mismatch, and mechanical instability. Considering the controllability and efficiency of the stimuli-responsive materials, physical fields such as, the temperature, chemicals, light, electric current, magnetic field, and pressure have been adopted as the external stimuli in practice. In this paper, the frontier works and the latest progress in AMMs from the aspects of the mechanics and materials are reviewed. The functions and engineering applications of the AMMs are also discussed. Finally, existing issues and future perspectives in this field are briefly described. This review is expected to provide the basis and inspiration for the follow-up research on AMMs.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.