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Updated: Jul 12, 2025
Bile Duct Ligation in Mice: Induction of Inflammatory Liver Injury and Fibrosis by Obstructive Cholestasis
Published on: February 10, 2015
Let-7 suppresses liver fibrosis by inhibiting hepatocyte apoptosis and TGF-β production
Jiahui Song1, Haining Lv2, Beibei Liu3
1Center of Reproductive Medicine, National Health Commission Key Laboratory of Advanced Reproductive Medicine and Fertility, Shengjing Hospital of China Medical University, Shenyang 110004, China.
Objective:
FAS-mediated apoptosis of hepatocytes and aberrant TGF-β signaling are major drivers of liver fibrosis. Decreased miRNA let-7 expression in the livers of patients and animals with fibrosis suggests a mechanistic link of let-7 to hepatic fibrogenesis.
Methods:
Using transient transfection we tested the effects of let-7 overexpression and TET3 siRNA knockdown on FAS and TGF-β1 expression and FAS-mediated apoptosis in human and mouse primary hepatocytes. We assessed the therapeutic activity of let-7 miRNA delivered via adeno-associated viral vectors in mouse models of carbon tetrachloride (CCl4)-induced and bile duct ligation (BDL)-induced liver fibrosis.
Results:
Let-7 decreased TGF-β1 production from hepatocytes through a negative feedback loop involving TET3. On the other hand, let-7 post-transcriptionally inhibits FAS expression, thereby suppressing hepatocyte apoptosis. Hepatic-specific delivery of let-7 miRNA mitigated liver fibrosis in both CCl4 and BDL mouse models.
Conclusions:
Let-7 is a crucial node in the signaling networks that govern liver fibrosis progression. Let-7 and/or its derivatives may be used as therapeutic agents for liver fibrosis.
Insights
MicroRNA let-7 combats liver fibrosis by reducing hepatocyte apoptosis and aberrant TGF-β signaling. This study demonstrates let-7
Area of Science:
- Hepatology and molecular biology
- Fibrosis research
- MicroRNA therapeutics
Background:
- Liver fibrosis is driven by hepatocyte apoptosis and aberrant transforming growth factor-beta (TGF-β) signaling.
- Decreased expression of microRNA let-7 in fibrotic livers suggests a role in hepatic fibrogenesis.
Purpose of the Study:
- To investigate the mechanistic link between let-7 and liver fibrosis.
- To evaluate let-7 as a potential therapeutic agent for liver fibrosis.
Main Methods:
- Overexpression and knockdown of let-7 and TET3 in primary hepatocytes.
- Assessment of FAS and TGF-β1 expression and apoptosis.
- In vivo studies using adeno-associated viral vectors for hepatic delivery of let-7 in mouse models of liver fibrosis (CCl4-induced and BDL-induced).
Main Results:
- Let-7 negatively regulates TGF-β1 production via a feedback loop involving TET3.
- Let-7 post-transcriptionally inhibits FAS expression, reducing hepatocyte apoptosis.
- Hepatic delivery of let-7 miRNA significantly mitigated liver fibrosis in mouse models.
Conclusions:
- Let-7 plays a critical role in regulating liver fibrosis progression.
- Let-7 and its derivatives show therapeutic potential for treating liver fibrosis.
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