The effect of hypoxia on liver cells in mouse liver fibrosis model
Date Issued
2014
Date
2014
Author(s)
Twu, Woan-Ing
Abstract
Hepatic fibrosis is the response of liver encountering chronic injury, which would often progress to liver cirrhosis or even hepatocellular carcinoma (HCC). Chronic liver disease and liver fibrosis were in the list of top tenth cause of death in both Taiwan and the US, but no effective drug was developed for the treatment of fibrosis.
The accumulation of extracellular matrix (ECM) during liver fibrosis would lead to hypoxia due to the blockage of oxygen diffusion, and hypoxia inducible factor 1 α (HIF1α) is the main modulator of hypoxic response. Here in my research, I have detected upregulated expression of HIF1α, in mRNA as well as in protein level in fibrotic liver. The cells expressing HIF1α also expressed epithelial cell adhesion
molecule (EpCAM), Albumin (Alb) and cytokeratin 19 (CK19), suggesting that these HIF1α + cells were hepatic progenitor cell (HPC)-like. I also observed translocated β-catenin in fibrotic liver, indicating the activation of canonical Wnt signal. These data proved that HPCs were localized in hypoxic area during liver fibrosis, and HIF1α may interact with Wnt/β-catenin signaling to regulate HPC.
As for the in vitro experiment, I cultured HCC cell line Huh7 under normoxic and hypoxic conditions to compare the expression levels of the genes mentioned in the in vivo experiment and found out that the mRNA expression level of HPC markers, EpCAM and CK19, and Wnt/β-catenin downstream targets, Axin2 and CyclinD1, were all elevated. Increased EpCAM and CK19 protein expression, in addition to β-catenin
translocation could also be observed in hypoxic cultured Huh7. These results suggested that the increased expression of HPC marker and Wnt/β-catenin signaling pathway observed in vivo could be regulated by hypoxic condition.
Subjects
肝纖維化
低氧
肝臟前驅細胞
EpCAM
HIF
Wnt/β-catenin
Type
thesis
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