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The role of AdipoR1 and AdipoR2 in liver fibrosis
Badr Alzahrani1, Tristan Iseli1, Mehdi Ramezani-Moghadam1
1The Storr Liver Centre, Westmead Institute of Medical Research, University of Sydney at Westmead Hospital, Westmead, New South Wales 2145, Australia.
Abstract:
Activation of the adiponectin (APN) signaling axis retards liver fibrosis. However, understanding of the role of AdipoR1 and AdipoR2 in mediating this response is still rudimentary. Here, we sought to elucidate the APN receptor responsible for limiting liver fibrosis by employing AdipoR1 and AdipoR2 knock-out mice in the carbon tetrachloride (CCl4) model of liver fibrosis. In addition, we knocked down receptor function in primary hepatic stellate cells (HSCs) in vitro. Following the development of fibrosis, AdipoR1 and AdipoR2 KO mice had no quantitative difference in fibrosis by Sirius red staining. However, AdipoR2 KO mice had an enhanced fibrotic signature with increased Col1-α1, TGFß-1, TIMP-1, IL-10, MMP-2 and MMP-9. Knockdown of AdipoR1 or AdipoR2 in HSCs followed by APN treatment demonstrated that AdipoR1 and AdipoR2 did not affect proliferation or TIMP-1 gene expression, while AdipoR2 modulated Col1-α1 and α-SMA gene expression, HSC migration, and AMPK activity. These finding suggest that AdipoR2 is the major APN receptor on HSCs responsible for mediating its anti-fibrotic effects.
Insights
Adiponectin (APN) signaling limits liver fibrosis. AdipoR2, not AdipoR1, is the primary APN receptor on hepatic stellate cells, mediating APN's anti-fibrotic effects by modulating key fibrotic markers and cell behavior.
Area of Science:
- Hepatology
- Cell Biology
- Molecular Medicine
Background:
- Liver fibrosis, a precursor to cirrhosis and liver cancer, involves the excessive accumulation of extracellular matrix components.
- Adiponectin (APN) signaling is recognized for its protective role against liver fibrosis, but the specific roles of its receptors, AdipoR1 and AdipoR2, remain unclear.
Purpose of the Study:
- To determine which adiponectin receptor (AdipoR1 or AdipoR2) mediates the anti-fibrotic effects of APN in the liver.
- To investigate the specific cellular and molecular mechanisms by which AdipoR1 and AdipoR2 influence liver fibrosis progression.
Main Methods:
- Utilized AdipoR1 and AdipoR2 knockout (KO) mice in a carbon tetrachloride (CCl4)-induced liver fibrosis model.
- Performed in vitro knockdown of AdipoR1 and AdipoR2 in primary hepatic stellate cells (HSCs) followed by APN treatment.
- Assessed fibrosis severity using Sirius red staining and quantified gene expression of fibrotic markers (Col1-α1, TGFß-1, TIMP-1, IL-10, MMP-2, MMP-9) and HSC activation markers (α-SMA).
Main Results:
- While AdipoR1 and AdipoR2 KO mice showed no significant difference in overall fibrosis, AdipoR2 KO mice exhibited an exacerbated fibrotic signature with increased expression of collagen, TGFß-1, TIMP-1, IL-10, MMP-2, and MMP-9.
- In vitro, AdipoR1 and AdipoR2 knockdown did not impact HSC proliferation or TIMP-1 expression.
- AdipoR2 knockdown significantly modulated Col1-α1 and α-SMA gene expression, impaired HSC migration, and altered AMPK activity, indicating a crucial role in HSC function.
Conclusions:
- AdipoR2 is identified as the predominant adiponectin receptor on hepatic stellate cells mediating the anti-fibrotic actions of APN.
- Targeting AdipoR2 may represent a therapeutic strategy for mitigating liver fibrosis progression.
