Lack of Nogo-B expression ameliorates PPAR. deficiency-aggravated liver fibrosis by regulating TLR4-NF-κB-TNF-α axis and macrophage polarization

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 (PPAR gamma) and Nogo-B play critical roles in fibrogenesis, while PPAR gamma is essential for the development. However, the effect of Nogo-B deficiency on the development of liver fibrosis in cell-specific PPAR. deficient mice remains unknown. In this study, hepatocyte or macrophage PPAR gamma deficient (hPPAR gamma KO or mPPAR gamma KO) mice, Nogo-B deficient mice, and cell-specific PPAR gamma plus Nogo-B double deficient (hPPAR gamma/Nogo-B DKO or mPPAR./Nogo-B DKO) mice were induced liver fibrosis by CCl4 injection. We found hPPAR. KO mice showed enhanced liver fibrotic signatures compared to mPPAR. KO mice after CCl4 administration. Hepatocyte or macrophage PPAR. deficiency further enhanced CCl4-induced severe inflammation infiltration, apoptosis and M1 macrophage polarization in the liver. In contrast, Nogo-B deficiency effectively ameliorated PPAR gamma deficiency-aggravated liver injury and fibrosis. It ameliorated PPAR gamma deficiency-aggravated liver inflammation and fibrosis by suppressing hepatic stellate cell activation, TLR4-NF-kappa B/TNF- alpha signaling and M1 macrophage polarization. In conclusion, our study demonstrates that PPAR gamma 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.

Automated summary

This study demonstrates the important roles of PPARγ and Nogo-B in liver fibrosis. PPARγ deficiency increases susceptibility of mice to CCl4-induced liver injury and fibrosis, while Nogo-B deficiency effectively attenuates this exacerbation effect. Therefore, Nogo-B inhibition may be a potential therapeutic approach for liver fibrosis treatment.