Quantitative Proteomic analysis on Activated Hepatic Stellate Cells reversion Reveal STAT1 as a key regulator between Liver Fibrosis and recovery

Zhang, Hongyu; Chen, Fangyan; Xu, Fan; Lin, Cong; Hao, Yunwei; Huang, Wei; Lin, Weiran; Jiang, Ying; He, Fuchu

doi:10.1038/srep44910

Cited by 22 publications

(15 citation statements)

References 36 publications

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“…In addition, the expression of GFAP, which partially indicates a quiescent state in stellate cells, is maintained by retinol 16 ; further, the expression of α-SMA (alpha smooth muscle actin), a sensitive and reliable marker of activation, is suppressed by OA 14 . These results suggest a potential role for lipid metabolism in the regulation of HSC activation, or vice versa, as demonstrated by recent in silico analyses 18 , 19 .…”

Section: Introductionsupporting

confidence: 77%

In vitro inhibition of hepatic stellate cell activation by the autophagy-related lipid droplet protein ATG2A

Hong

Wang

et al. 2018

Sci Rep

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Clinical studies have found that moderate intake of retinol or oleic acid can enlarge the lipid droplets of hepatic stellate cells and suppress their activation. However, the link between lipid droplets and cell activation is unknown. This study compared the dynamics of lipid droplet-associated protein expression between activated and reverted stellate cells. Reversion of the activated human stellate cell line LX-2 and inhibition of primary mouse stellate cell activation were induced by retinol or oleic acid, which resulted in larger lipid droplets and the downregulation of cell activation markers. Quantitative proteomics and immunoblotting were performed to compare lipid-droplet protein profiles between activated and reverted LX-2 cells. Compared to expression in activated cells, 50 lipid-droplet proteins were upregulated, whereas 28 were downregulated upon reversion. ATG2A was significantly enriched in lipid droplets of retinol/oleic acid-treated LX-2 cells and quiescent primary stellate cells. Reduced expression of α-SMA, increased expression of perilipin-3, enlarged lipid droplets, and suppression of autophagic flux were observed in ATG2A-deficient LX2 cells. Lipid-droplet protein profile changes during the reversion of activated stellate cells might provide new insights into the molecular mechanisms linking lipid droplets to liver fibrosis. ATG2A could represent a potential new drug target for hepatic fibrosis.

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Section: Introductionsupporting

confidence: 77%

In vitro inhibition of hepatic stellate cell activation by the autophagy-related lipid droplet protein ATG2A

Hong

Wang

et al. 2018

Sci Rep

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“…These results further supports the hypothesis that STAT1 is an essential protein participating in EMT induced by HG and a crucial effector downstream of FoxO1. Our findings are consistent with the notion that a significant increase in STAT1 contributes to renal fibrosis and the production of profibrotic cytokine through TGF-β1 [37], as well as with the critical role of STAT1 in the progression of liver fibrosis and the fact that suppression of STAT1promotes the reversion of liver fibrosis and recovery [38].…”

Section: Discussionsupporting

confidence: 91%

FoxO1-mediated inhibition of STAT1 alleviates tubulointerstitial fibrosis and tubule apoptosis in diabetic kidney disease

et al. 2019

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Background: Tubulointerstitial fibrosis (TIF) plays an important role in the progression of diabetic kidney disease (DKD). Forkhead box O1 (FoxO1) is involved in the regulation of metabolism and cell apoptosis, but its function in renal TIF induced by DKD is less well understood. Methods: Human kidney biopsies with DKD and normal controls were used to detect apoptosis and TIF induced by diabetes. A mouse model with kidney-specific overexpression of Pax2-3aFoxO1 was established to further investigate the functions of FoxO1 in vivo. The in vitro roles of FoxO1 were analyzed in HK-2 cells with 3aFoxO1-knockin (3aFoxO1-KI) or FoxO1-knockdown (FoxO1-KD) via CRISPR/Cas9. Western blot, immunohistochemistry, and chromatin immunoprecipitation were used to explore the underlying mechanisms. Findings: In this study, DKD patients had increased renal TIF and apoptosis. In vivo study showed that kidney-specific overexpression of Pax2-3aFoxO1 significantly reduced the expression of p-STAT1 with resultant renal functional impairment, retarding renal TIF and apoptosis in diabetic mice. Meanwhile, We observed that FoxO1-KD in HK-2 cells aggravated the expression of p-STAT1, leading to activation of epithelial-to-mesenchymal transition (EMT) and intrinsic apoptotic pathway. Conversely, EMT and apoptosis were significantly attenuated in HK-2 cells with 3aFoxO1-KI under hyperglycemic conditions. Interpretation: Taken together, these data suggest that the protection role of FoxO1 against renal TIF and apoptosis in DKD is likely in part to target STAT1 signaling, which may be a promising strategy for longterm treatment of DKD.

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“…Increasing evidence suggests that signalling through Janus kinase-signal transducer and activator of transcription (JAK-STAT) pathways plays key roles in controlling chronic liver injury progression and liver regeneration 9. Interestingly, STAT1 and STAT3 activation takes place in both parenchymal and non-parenchymal cells, playing contrasting roles in fundamental aspects of liver pathophysiology 10.…”

Section: Introductionmentioning

confidence: 99%

Rilpivirine attenuates liver fibrosis through selective STAT1-mediated apoptosis in hepatic stellate cells

Martí-Rodrigo

Alegre

Moragrega

et al. 2019

Gut

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ObjectiveLiver fibrosis constitutes a major health problem worldwide due to its rapidly increasing prevalence and the lack of specific and effective treatments. Growing evidence suggests that signalling through cytokine-activated Janus kinase (JAK)-signal transducer and activator of transcription (STAT) pathways regulates liver fibrosis and regeneration. Rilpivirine (RPV) is a widely used anti-HIV drug not reported to produce hepatotoxicity. We aimed to describe the potential hepatoprotective effects of RPV in different models of chronic liver injury, focusing on JAK-STAT signalling regulation.DesignThe effects of RPV on hepatic steatosis, inflammation and fibrogenesis were studied in a nutritional mouse model of non-alcoholic fatty liver disease, carbon tetrachloride-induced fibrosis and bile duct ligation-induced fibrosis. Primary human hepatic stellate cells (hHSC) and human cell lines LX-2 and Hep3B were used to investigate the underlying molecular mechanisms.ResultsRPV exerted a clear anti-inflammatory and antifibrotic effect in all the in vivo models of liver injury employed, and enhanced STAT3-dependent proliferation in hepatocytes and apoptosis in HSC through selective STAT1 activation. These results were reproduced in vitro; RPV undermined STAT3 activation and triggered STAT1-mediated pathways and apoptosis in HSC. Interestingly, this selective pro-apoptotic effect completely disappeared when STAT1 was silenced. Conditioned medium experiments showed that HSC apoptosis activated STAT3 in hepatocytes in an interleukin-6-dependent mechanism.ConclusionRPV ameliorates liver fibrosis through selective STAT1-dependent induction of apoptosis in HSC, which exert paracrinal effects in hepatocytes, thus promoting liver regeneration. RPV’s actions may represent an effective strategy to treat chronic liver diseases of different aetiologies and help identify novel therapeutic targets.

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Quantitative Proteomic analysis on Activated Hepatic Stellate Cells reversion Reveal STAT1 as a key regulator between Liver Fibrosis and recovery

Cited by 22 publications

References 36 publications

In vitro inhibition of hepatic stellate cell activation by the autophagy-related lipid droplet protein ATG2A

In vitro inhibition of hepatic stellate cell activation by the autophagy-related lipid droplet protein ATG2A

FoxO1-mediated inhibition of STAT1 alleviates tubulointerstitial fibrosis and tubule apoptosis in diabetic kidney disease

Rilpivirine attenuates liver fibrosis through selective STAT1-mediated apoptosis in hepatic stellate cells

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