Jnk1 in murine hepatic stellate cells is a crucial mediator of liver fibrogenesis

肝星状细胞 天狼星红 肝细胞 纤维化 生物 分子生物学 库普弗电池 病理 内分泌学 内科学 化学 医学 免疫学 生物化学 体外
作者
Gang Zhao,Maximilian Hatting,Yulia A. Nevzorova,Peng Jin,Wei Hu,Mark V. Boekschoten,Tania Roskams,Michael Müller,Nikolaus Gaßler,Christian Liedtke,Roger J. Davis,Francisco Javier Cubero,Christian Trautwein
出处
期刊:Gut [BMJ]
卷期号:63 (7): 1159-1172 被引量:49
标识
DOI:10.1136/gutjnl-2013-305507
摘要

Objective

The c-Jun N-terminal kinase-1 (Jnk1) gene has been shown to be involved in liver fibrosis. Here, we aimed to investigate the molecular mechanism and define the cell type involved in mediating the Jnk1-dependent effect on liver fibrogenesis.

Design

Jnk1f/f wildtype (WT), Jnk1−/− and Jnk1Δhepa (hepatocyte-specific deletion of Jnk1) mice were subjected to (i) bile duct ligation (BDL) and (ii) CCl4-induced liver fibrosis. Additionally, we performed bone marrow transplantations (BMT), isolated primary hepatic stellate cells (HSCs), studied their activation in vitro and investigated human diseased liver samples.

Results

Phosphorylated Jnk was expressed in myofibroblasts, epithelial and inflammatory cells during the progression of fibrogenesis in humans and mice. In mice, liver transaminases, alkaline phosphatase, bilirubin and liver histology revealed reduced injury in Jnk1−/− compared with WT and Jnk1Δhepa mice correlating with lower hepatocyte cell death and proliferation. Consequently, parameters of liver fibrosis such as Sirius red staining and collagen IA1 and α-smooth muscle actin expression were downregulated in Jnk1−/− compared with WT and Jnk1Δhepa livers, 4 weeks after CCl4 or BDL. BMT experiments excluded bone marrow–derived cells from having a major impact on the Jnk1-dependent effect on fibrogenesis, while primary HSCs from Jnk1−/− livers showed reduced transdifferentiation and extracellular matrix production. Moreover, Jnk1 ablation caused a reduced lifespan and poor differentiation of HSCs into matrix-producing myofibroblasts.

Conclusions

Jnk1 in HSCs, but not in hepatocytes, significantly contribute to liver fibrosis development, identifying Jnk1 in HSCs as a profibrotic kinase and a promising cell-directed target for liver fibrosis.
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