Dual regulation of HMGB1 by combined JNK1/2–ATF2 axis with miR‐200 family in nonalcoholic steatohepatitis in mice

In the context of diabetes, obesity, and metabolic syndrome, the inflammatory signaling has critical roles in the pathogenesis of nonalcoholic fatty liver disease (NAFLD), but the underlying mechanisms remain poorly delineated. Herein, early and persistently elevated, proinflammatory cytokine HMGB1 expression was detected in a high‐fat diet (HFD)‐induced NAFLD model in C57BL/6 mice. The expression and extracellular release of HMGB1 was rapidly and dramatically induced by saturated palmitic acid in vitro. HFD‐induced inflammatory response and liver function impairment were both mitigated after the inhibition of endogenous HMGB1 by neutralizing antibody in vivo. The up‐regulation of HMGB1 was thought to be modified by dual channels: in the transcriptional level, it was regulated by JNK1/JNK2‐ATF2 axis; post‐transcriptionally, it was regulated by the microRNA (miR)‐200 family, especially miR‐429. miR‐429 liver conditional knockout mice (miR‐429 μhep ), fed either a normal diet or an HFD, showed severe liver inflammation and dysfunction, accompanied by greater expression of HMGB1. Intriguingly, the up‐regulation and release of HMGB1 could in turn self‐activate TLR4–JNK1/JNK2–ATF2 signaling, thus forming a positive feedback. Our findings reveal a novel mechanism by which HMGB1 expression was regulated by both the JNK1/2–ATF2 axis and the miR‐200 family, which provides a potential new approach for the treatment of NAFLD.—Chen, X., Ling, Y., Wei, Y., Tang, J., Ren, Y., Zhang, B., Jiang, F., Li, H., Wang, R., Wen, W., Lv, G., Wu, M., Chen, L., Li, L., Wang, H. Dual regulation of HMGB1 by combined JNK1/2–ATF2 axis with miR‐200 family in nonalcoholic steatohepatitis in mice. FASEB J. 32, 2722–2734 (2018). www.fasebj.org