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Published on: March 11, 2017
JTCD attenuates HF by inhibiting activation of HSCs through PPARα-TFEB axis-mediated lipophagy
Chang Shao1, Wenfang Lan1, Ying Ding1
1School of Basic Medical Sciences, Zhejiang Chinese Medical University, Hangzhou 310053, China.
Insights
Jiawei Taohe Chengqi Decoction (JTCD) alleviates hepatic fibrosis (HF) by inhibiting lipophagy, the degradation of lipid droplets in hepatic stellate cells (HSCs). This effect is mediated through the regulation of the PPARα/TFEB signaling pathway.
Area of Science:
- Hepatology
- Cell Biology
- Pharmacology
Background:
- Hepatic fibrosis (HF) is a reversible stage of chronic liver disease.
- Activation of hepatic stellate cells (HSCs) and lipid droplet (LD) degradation are key to HF progression.
- Jiawei Taohe Chengqi Decoction (JTCD) shows potential in inhibiting HSC activation during HF, but its mechanism is unclear.
Purpose of the Study:
- To investigate if JTCD inhibits lipophagy in HF.
- To explore JTCD's mechanism in HF via the PPARα/TFEB axis in HSCs.
Main Methods:
- Network pharmacology and molecular docking predicted JTCD's mechanism.
- In vivo studies used a carbon tetrachloride (CCl4)-induced mouse model of HF.
- In vitro studies utilized LX-2 cells treated with TGF-β, agonists/antagonists of PPARα, and TFEB siRNA.
Main Results:
- JTCD alleviated CCl4-induced HF in mice, reducing HF markers (α-SMA, COL1A1).
- JTCD inhibited PPARα expression and lipophagy in vivo.
- JTCD delayed LD degradation and reduced lipophagy in LX-2 cells, implicating PPARα/TFEB signaling.
Conclusions:
- JTCD demonstrates therapeutic potential for hepatic fibrosis.
- JTCD inhibits lipophagy by regulating the PPARα/TFEB signaling pathway in HSCs.
- This study elucidates a novel mechanism for JTCD in treating HF.
Background:
Hepatic fibrosis (HF) is an intermediate stage in the progression of chronic liver disease to cirrhosis and has been shown to be a reversible pathological process. Known evidence suggests that activation of hepatic stellate cells (HSCs) and degradation of their lipid droplets (LDs) play an indispensable role in the process of HF. Jiawei Taohe Chengqi Decoction (JTCD) can inhibit the activation of HSCs in the process of HF, but the exact mechanism remains to be elucidated.
Purpose:
The aim of this study is to determine whether JTCD inhibits lipophagy and to explore the possible mechanisms of its HF effect in HSCs by regulating the PPARα/TFEB axis.
Methods:
Network pharmacology and molecular docking were firstly applied to predict the potential mechanism of JTCD for the treatment of HF. In vivo, a mouse model of HF was constructed using carbon tetrachloride (CCl4) solution, and the efficacy of JTCD was assessed by staining of pathological sections, oil red O staining, immunofluorescence (IF), immunohistochemistry (IHC) staining, Western blotting and qRT-PCR. The intervention of JTCD was verified in vitro by induction of activated LX-2 cells with TGF-β solution and intervention using agonists and antagonists of PPARα. Finally, transient transfection of cells using TFEB siRNA was performed for validation studies.
Results:
JTCD effectively alleviated CCl4-induced HF in mice and reduced the levels of HF markers α-smooth muscle actin (α-SMA) and collagen I (COL1A1), and inhibited PPARα expression and lipophagy process. In vitro, JTCD delayed the degradation of LDs and reduced lipophagy in LX-2 cells, suggesting a mechanism involving PPARα/TFEB axis signaling regulation.
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