Lack of Nogo-B expression ameliorates PPARγ deficiency-aggravated liver fibrosis by regulating TLR4-NF-κB-TNF-α axis and macrophage polarization
Dan Zhao, Chao Xue, Yanfang Yang, Jiaqi Li, Xiaolin Wang, Yi Chen, Shuang Zhang, Yuanli Chen, Yajun Duan, Xiaoxiao Yang, Jihong Han
Abstract
Liver fibrosis is an important pathologic process in response to chronic or repetitive liver injury. It can advance to liver cirrhosis. Both peroxisome proliferator-activated receptor gamma (PPARγ) and Nogo-B play critical roles in fibrogenesis, while PPARγ is essential for the development. However, the effect of Nogo-B deficiency on the development of liver fibrosis in cell-specific PPARγ deficient mice remains unknown. In this study, hepatocyte or macrophage PPARγ deficient (hPPARγ KO or mPPARγ KO) mice, Nogo-B deficient mice, and cell-specific PPARγ plus Nogo-B double deficient (hPPARγ/Nogo-B DKO or mPPARγ/Nogo-B DKO) mice were induced liver fibrosis by CCl4 injection. We found hPPARγ KO mice showed enhanced liver fibrotic signatures compared to mPPARγ KO mice after CCl4 administration. Hepatocyte or macrophage PPARγ deficiency further enhanced CCl4-induced severe inflammation infiltration, apoptosis and M1 macrophage polarization in the liver. In contrast, Nogo-B deficiency effectively ameliorated PPARγ deficiency-aggravated liver injury and fibrosis. It ameliorated PPARγ deficiency-aggravated liver inflammation and fibrosis by suppressing hepatic stellate cell activation, TLR4-NF-κB/TNF-α signaling and M1 macrophage polarization. In conclusion, our study demonstrates that PPARγ deficiency increases susceptibility of mice to develop CCl4-induced liver injury/fibrosis, which is potently reduced by Nogo-B deficiency, indicating Nogo-B inhibition might be a therapeutic approach for liver fibrosis treatment.