Abstract
Bnip3, which is regulated by Hif-1 in cells under oxygen deprivation, is a death related protein associated with autophagy and apoptosis. Hif-1 was reported to regulate autophagy to activate hepatic stellate cells (HSCs), while the specific molecular mechanism is vague. The possible mechanism of Hif-1 regulating autophagy of HSCs via Bnip3 was explored in this study. Bnip3 was detected in fibrotic liver tissues from humans and mice. Hif-1 was inhibited by chemical inhibitor and Bnip3 was detected in activated HSCs. The co-localization of Bnip3 and LC3B was captured by confocal microscopy and autophagic flow was assessed in Bnip3 siRNA transfected cells. Bnip3 interacted proteins were screened with mass spectrometry. The interaction of Bnip3 and vimentin was detected with co-immunoprecipitation and confocal microscopy. The results showed that Bnip3 was increased in fibrotic liver tissues and activated HSCs. Hif-1 inhibition suppressed Bnip3 expression in activated HSCs. Bnip3 was partially co-localized with autophagosomes and Bnip3 inhibition suppessed autophagy in activated HSCs. Bnip3 interacted with vimentin and Bnip3 expression was inhibited as vimentin was inhibited in activated HSCs. Conclusively, this study indicated that Bnip3 promoted autophagy and activation of HSCs, via interacting with vimentin, an intermediate filament protein with highly abundant expression in HSCs.
Highlights
Liver fibrosis is characterized by excessive scar formation due to overproduction and deposition of the extracellular matrix (ECM) [1]
Bcl-2/adenovirus E1B 19-kDa interacting protein (Bnip3) was detected in fibrotic liver tissues of mice infected with S. japonicum, which was recognized as an animal model of infective fibrosis [17,18,19,20]
We have previously determined that Hypoxia inducible factor-1 (Hif-1), hypoxia inducible factor-1, affects the activation of hepatic stellate cells by regulating autophagy [17, 18, 20]
Summary
Liver fibrosis is characterized by excessive scar formation due to overproduction and deposition of the extracellular matrix (ECM) [1]. Hepatic stellate cells (HSCs) were identified as the key cellular source of extracellular matrix in the liver. Upon acute or chronic liver damage, HSCs transdifferentiate from quiescent, www.aging-us.com lipid droplet-containing cells toward myofibroblast-like cells, which were characterized by a decreased number of lipid droplets, increased proliferation, increased expression of vimentin and α-smooth muscle actin (αSMA), enhanced synthesis of ECM [2]. By which cells degrade and metabolize their own constituents, is an evolutionary conserved fundamental cellular process. Autophagosomes fuse with lysosomes to form autophagolysosomes, which degrade the contents to adapt cellular metabolic requirement or remove damaged organelles [3,4,5]. Recent studies have determined that, during the activation of HSCs upon liver damage, different autophagic mechanisms including classical macro-autophagy, mitophagy, lipophagy, and multiple organelles including mitochondria, lipid droplets and endoplasmic reticulum, are involved [6,7,8,9], illustrating that HSC activation is a complex and sophisticated process, which remains unclear
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