The Storr Liver Centre, Westmead Institute of Medical Research, University of Sydney at Westmead Hospital, Westmead, New South Wales 2145, Australia.
Department of Molecular and Cell Biology, Centre for Comparative Genomics, The Centre for Biodiscovery and Molecular Development of Therapeutics, James Cook University, Australian Institute of Tropical Health and Medicine, Townsville, QLD, 4811, Australia.
Biochim Biophys Acta Mol Basis Dis. 2018 Mar;1864(3):700-708. doi: 10.1016/j.bbadis.2017.12.012. Epub 2017 Dec 10.
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 (CCl) 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.
脂联素 (APN) 信号轴的激活可延缓肝纤维化。然而，对于 AdipoR1 和 AdipoR2 在介导这种反应中的作用的理解仍然很初步。在这里，我们通过在四氯化碳 (CCl) 肝纤维化模型中使用 AdipoR1 和 AdipoR2 敲除小鼠，试图阐明负责限制肝纤维化的 APN 受体。此外，我们在体外敲低了原代肝星状细胞 (HSCs) 中的受体功能。在纤维化发展后，AdipoR1 和 AdipoR2 KO 小鼠的天狼星红染色纤维化无定量差异。然而，AdipoR2 KO 小鼠的纤维化特征增强，Col1-α1、TGFß-1、TIMP-1、IL-10、MMP-2 和 MMP-9 增加。在 HSCs 中敲低 AdipoR1 或 AdipoR2 后再用 APN 处理表明，AdipoR1 和 AdipoR2 不影响增殖或 TIMP-1 基因表达，而 AdipoR2 调节 Col1-α1 和 α-SMA 基因表达、HSC 迁移和 AMPK 活性。这些发现表明，AdipoR2 是 HSCs 上的主要 APN 受体，负责介导其抗纤维化作用。
