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

Abstract

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 intrahepatic HMGB1 signal in hepatitis B virus (HBV)-related liver fibrosis progression, and presented a 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 (TEM) 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 extracellular regulated protein kinase (ERK)/c-Jun N-terminal kinase (JNK) mitogen-activated protein kinase (MAPK) and restrained mammalian target of rapamycin (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 LC3-siRNA transfected LX-2, we found HMGB1-induced fibrogenesis is dependent on its autophagy-inducing effects. Finally, we elucidated the involvement of extracellular HMGB1-receptor for advenced glycation end product (RAGE) axis and endogenous HMGB1 in exogenous HMGB1-induced effects. Our findings could open new perspectives in developing an antifibrotic therapy by targetting the HSCs autophagy.

Long noncoding RNA XIST enhances ethanol‐induced hepatic stellate cells autophagy and activation via miR‐29b/HMGB1 axis

“…The working model of HMGB1‐induced HSCs autophagy and fibrogenesis may be summarized as follows: In response to liver injury induced by chronic HBV infection, necrotic hepatocytes passively release HMGB1, which HMGB1 binds to receptor for advanced glycation end product (RAGE) in a paracrine manner, and induces HSCs autophagy and activation, via activation of p‐ERK/JNK MAPK and inhibition of p‐STAT3 and p‐mTOR signaling proteins. Meanwhile, activated HSCs actively secrete HMGB1, which may bind to their RAGE in an autocrine manner, as a positive feedback of exogenous HMGB1 . In this study, we found that both miR‐29b mimic and HMGB1 knockdown blocked the XIST overexpression‐mediated HSCs autophagy and activation.…”

“…In addition, HMGB1 is markedly increased in fibrotic liver diseases and plays a pivotal role in liver fibrosis . Recent evidence has indicated that HMGB1 induces autophagy and thus facilitates HSCs activation and liver fibrosis . The working model of HMGB1‐induced HSCs autophagy and fibrogenesis may be summarized as follows: In response to liver injury induced by chronic HBV infection, necrotic hepatocytes passively release HMGB1, which HMGB1 binds to receptor for advanced glycation end product (RAGE) in a paracrine manner, and induces HSCs autophagy and activation, via activation of p‐ERK/JNK MAPK and inhibition of p‐STAT3 and p‐mTOR signaling proteins.…”

“…Evidence indicates that miR‐29b‐3p targeted and inhibited expression of high‐mobility group box‐1 (HMGB1) . Notably, HMGB1 has been reported to induce autophagy and thus facilitate HSCs activation and liver fibrosis . Thus, we may suggest that XIST functions as a ceRNA for miR‐29b to facilitate HMGB1 expression, thus inducing autophagy and facilitating HSCs activation and liver fibrosis.…”

“…Autophagy has been found induced in the carbon tetrachloride (CCl 4 )‐induced cirrhosis model mice . Furthermore, activation of autophagy causes HSCs activation . Our previous study demonstrated that inhibition of autophagy reversed alcohol‐induced HSCs activation and alleviated alcoholic fatty liver injury in ALF model mice …”

Bouchardatine analogue alleviates non‐alcoholic hepatic fatty liver disease/non‐alcoholic steatohepatitis in high‐fat fed mice by inhibiting ATP synthase activity

“…Fibrosis has received increasingly more attention as a critical pathological feature of NASH because the extent of fibrosis is a major factor for the prognosis of NASH (Chalasani et al, 2018;Diehl & Day, 2017;Drew, 2017). Hepatic fibrosis is pathologically characterized by collagen accumulation in the liver produced by activated stellate cells (Li et al, 2018;Tsuchida & Friedman, 2017). In the present study, the prolonged HF feeding markedly increased the collagen content However, due to the limitation of the lack of histological fibrosis in FIGURE 7 R17 attenuates NAFLD/NASH by activating the AMPK pathway with ATP synthase as an upstream target.…”