HMGB1-induced autophagy facilitates hepatic stellate cells activation: a new pathway in liver fibrosis

High-mobility group box-1 (HMGB1) plays a context-dependent role in autophagy, which is required for hepatic stellate cells (HSCs) activation. However, the significance of HMGB1-induced HSCs autophagy in liver fibrosis has not been elucidated. Here, we first documented an enrichment of peripheral and intra-hepatic HMGB1 signal in hepatitis B virus (HBV)-related liver fibrosis progression, and presented the direct evidence of anatomic proximity of HMGB1 with a-SMA (a marker for HSCs activation) in cirrhotic liver specimens. Then, we demonstrated the autophagy-inducing effects by serum-sourced HMGB1 in both primary murine HSCs and human HSCs cell line (LX-2), reflected by increased number of autophagic vacuoles (AVs) under the transmission electron microscope and up-regulated protein expression of lipidated microtubule-associated light chain 3 (LC3-II) (a marker for autophagosome) in western blot analysis. Intriguingly, there is a possible translocation of endogenous HMGB1 from the nucleus to cytoplasm to extracellular space, during exogenous HMGB1-induced HSCs autophagy. Meanwhile, the dose- and time-dependent effects by recombinant HMGB1 (rHMGB1) in enhancing LX-2 autophagy and fibrogenesis have been revealed with activated ERK/JNK MAPK and restrained mTOR/STAT3 signaling pathways. Additionally, the ERK or JNK inhibitor could not only inhibit rHMGB1-induced autophagy and fibrogenesis in LX-2 cells, but also restore the suppressed mTOR and STAT3 pathways. Furthermore, using LC...

Source: Clinical Science - June 15, 2018 Category: Biomedical Science Authors: Li, J., Zeng, C., Zheng, B., Liu, C., Tang, M., Jiang, Y., Chang, Y., Song, W., Wang, Y., Yang, C. Tags: PublishAheadOfPrint Source Type: research