Mechanisms of fibrosis in acute liver failure.
OBJECTIVE
Acute liver failure (ALF) is a condition with high mortality and morbidity. Fibrosis in chronic liver disease was extensively researched, whereas fibrosis and underlying mechanism in acute liver failure remains unclear.


METHODS
Hepatitis B virus related ALF patients were recruited to investigate if there was ongoing fibrosis by liver histology and liver stiffness measurement(LSM) analysis as well as fibrosis markers assay. Sera HMGB1 were kinetically detected in progression and remission stage of ALF. Hepatic stellate cell(HSC) activation by HMGB1 was explored by testing mRNA and protein level of α-SMA and collagen 1a1 by using qPCR and western blot. Autophagy induction by HMGB1 was explored by LC3-II conversion, autophagy flux and fluorescence.


RESULTS
Firstly, ongoing fibrosis in progression stage of ALF was confirmed by histological analysis, LS measurement as well as fibrosis markers detection. HSC activation and autophagy induction in explanted liver tissue also revealed. Next, kinetic monitoring sera HMGB1 revealed elevated HMGB1 in progression stage of ALF vs HBsAg carrier, and drop back to base level in remission stage. Thirdly, rHMGB1 dose dependently activated HSCs, as indicated by increased mRNA and proteins level in α-SMA and collagen 1a1. Moreover, autophagy was induced in HSC treated with rHMGB1, as illustrated by increased LC3 lipidation, elevated autophagy flux and GFP-LC3 puncta.


CONCLUSIONS
Acute liver failure is accompanied by ongoing fibrosis, HSC activation and autophagy induction. Increased HMGB1 activates HSC via autophagy induction. Those findings integrate HMGB1, HSCs activation, autophagy into a common framework that underlies the fibrosis in ALF.
Department of Infectious Diseases, First Affiliated Hospital, School of Medicine, Xi'an Jiaotong University, Xi'an, Shaanxi Province, China.|Institution of Hepatology, First Affiliated Hospital, School of Medicine, Xi'an Jiaotong University, Xi'an, Shaanxi province, China.
Yingli
Y
He
Institution of Hepatology, First Affiliated Hospital, School of Medicine, Xi'an Jiaotong University, Xi'an, Shaanxi province, China.
Li
L
Jin
Institution of Hepatology, First Affiliated Hospital, School of Medicine, Xi'an Jiaotong University, Xi'an, Shaanxi province, China.
Jing
J
Wang
Institution of Hepatology, First Affiliated Hospital, School of Medicine, Xi'an Jiaotong University, Xi'an, Shaanxi province, China.|Department of Infectious Diseases, Second teaching hospital of ShanDong university, Jinan, Shandong province, China.
Zhi
Z
Yan
Department of Infectious Diseases, First Affiliated Hospital, School of Medicine, Xi'an Jiaotong University, Xi'an, Shaanxi Province, China.|Institution of Hepatology, First Affiliated Hospital, School of Medicine, Xi'an Jiaotong University, Xi'an, Shaanxi province, China.
Tianyan
T
Chen
Department of Infectious Diseases, First Affiliated Hospital, School of Medicine, Xi'an Jiaotong University, Xi'an, Shaanxi Province, China.|Institution of Hepatology, First Affiliated Hospital, School of Medicine, Xi'an Jiaotong University, Xi'an, Shaanxi province, China.
Yingren
Y
Zhao
D000199:Actins / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001343:Autophagy; D015415:Biomarkers / Q000097:blood; D001706:Biopsy; D002478:Cells, Cultured; D024042:Collagen Type I / Q000235:genetics / Q000378:metabolism; D000090602:Collagen Type I, alpha 1 Chain; D018450:Disease Progression; D054459:Elasticity Imaging Techniques; D024243:HMGB1 Protein / Q000097:blood; D055166:Hepatic Stellate Cells / Q000378:metabolism / Q000473:pathology* / Q000821:virology; D006509:Hepatitis B / Q000150:complications* / Q000175:diagnosis; D006801:Humans; D008099:Liver / Q000378:metabolism / Q000473:pathology* / Q000821:virology; D008103:Liver Cirrhosis / Q000097:blood / Q000175:diagnosis* / Q000235:genetics / Q000473:pathology / Q000821:virology; D017114:Liver Failure, Acute / Q000097:blood / Q000175:diagnosis* / Q000235:genetics / Q000473:pathology / Q000821:virology; D008869:Microtubule-Associated Proteins / Q000235:genetics / Q000378:metabolism; D011237:Predictive Value of Tests; D011446:Prospective Studies; D051381:Rats; D015398:Signal Transduction
D000199:Actins; D015415:Biomarkers; D024042:Collagen Type I; D000090602:Collagen Type I, alpha 1 Chain; D024243:HMGB1 Protein; D008869:Microtubule-Associated Proteins; C541116:ACTA2 protein, human; C585491:HMGB1 protein, human; C526109:Anxa3 protein, rat; C477012:MAP1LC3A protein, human; C498862:Acta2 protein, rat
acute liver failure; autophagy; fibrosis; hepatic stellate cell; hepatitis B virus; high mobility group box 1