Abstract
Hepatic fibrosis is caused by exaggerated wound healing response to chronic injury, which eventually leads to hepatic cirrhosis. Differentiation of hepatic stellate cells (HSCs) to myofibroblast-like cells by inflammatory cytokines is the critical step in fibrosis. This step is accompanied by enlargement of the endoplasmic reticulum (ER) and Golgi apparatus, suggesting that protein synthesis and secretion are augmented in the activated HSCs. However, the process of rearrangement of secretory organelles and their functions remain to be fully elucidated. Here, we revealed that differentiation alters early secretory gene expression. We observed significant isoform-specific upregulation of the inner coat protein complex II (COPII) components, Sec23A and Sec24D, via the transmembrane bZIP transcription factor, CREB3L2/BBF2H7, during HSC activation. Moreover, knockdown of these components abrogated the activation, suggesting that Sec23A/Sec24D-mediated ER to Golgi trafficking is required for HSC activation.
Highlights
Hepatic fibrosis is considered as an exaggerated wound healing process in response to chronic liver injury, which is characterized by excessive extracellular matrix production
hepatic stellate cells (HSCs) cultured for 10 days showed significantly higher expression of collagen I and α-smooth muscle actin (α-SMA) compared with the 1-day-cultured cells, indicating that the cells differentiated into activated myofibroblasts (Fig. 1a)[11]
After starvation for 24 h with DMEM supplemented with 0.5% FBS, the cells were untreated or treated with 1 ng/ml TGF-β1 and cultured for 3 days
Summary
Hepatic fibrosis is considered as an exaggerated wound healing process in response to chronic liver injury, which is characterized by excessive extracellular matrix production. The differentiation is accompanied by enlargement of the endoplasmic reticulum (ER) and Golgi apparatus, suggesting that protein synthesis and secretion are enhanced in the activated HSCs4, 5. These enlargements of secretory organelles should alter the expression of early secretory gene components, this process remains to be fully elucidated. When cargoes are captured by cargo receptors, the pre-budding complex interacts with outer-coat complex Sec13/Sec[31], which enhances the hydrolysis of Sar[1] to complete the vesicle formation[6]. Depletion of Sar[1], Sec23A, Sec24D or CREB3L2/BBF2H7 hindered transforming growth factor β (TGF-β)-mediated HSC activation, suggesting that COPII-mediated transport via Sec23A/Sec24D is required for HSC activation
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