Joint National Laboratory for Antibody Drug Engineering, the First Affiliated Hospital of Henan University, Kaifeng, China; College of Life Sciences, State Key Laboratory of Medicinal Chemical Biology, Key Laboratory of Bioactive Materials of Ministry of Education, Nankai University, Tianjin, China.
College of Life Sciences, State Key Laboratory of Medicinal Chemical Biology, Key Laboratory of Bioactive Materials of Ministry of Education, Nankai University, Tianjin, China.
Biomed Pharmacother. 2022 Sep;153:113444. doi: 10.1016/j.biopha.2022.113444. Epub 2022 Jul 21.
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 CCl injection. We found hPPARγ KO mice showed enhanced liver fibrotic signatures compared to mPPARγ KO mice after CCl administration. Hepatocyte or macrophage PPARγ deficiency further enhanced CCl-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 CCl-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.
肝纤维化是对慢性或反复肝损伤的一种重要病理过程。它可以进展为肝硬化。过氧化物酶体增殖物激活受体 γ（PPARγ）和 Nogo-B 在纤维化中都起着关键作用，而 PPARγ 是其发展所必需的。然而，Nogo-B 缺乏对细胞特异性 PPARγ 缺陷小鼠肝纤维化发展的影响尚不清楚。在这项研究中，通过 CCl 注射诱导肝细胞或巨噬细胞 PPARγ 缺陷（hPPARγ KO 或 mPPARγ KO）小鼠、Nogo-B 缺陷小鼠和细胞特异性 PPARγ 加 Nogo-B 双缺陷（hPPARγ/Nogo-B DKO 或 mPPARγ/Nogo-B DKO）小鼠发生肝纤维化。我们发现，与 mPPARγ KO 小鼠相比，CCl 给药后 hPPARγ KO 小鼠表现出增强的肝纤维化特征。肝细胞或巨噬细胞 PPARγ 缺陷进一步增强了 CCl 诱导的严重炎症浸润、凋亡和 M1 巨噬细胞极化。相比之下，Nogo-B 缺乏有效地改善了 PPARγ 缺陷加重的肝损伤和纤维化。它通过抑制肝星状细胞激活、TLR4-NF-κB/TNF-α 信号和 M1 巨噬细胞极化，改善了 PPARγ 缺陷加重的肝炎症和纤维化。总之，我们的研究表明，PPARγ 缺陷增加了小鼠对 CCl 诱导的肝损伤/纤维化的易感性，而 Nogo-B 缺乏则有力地降低了这种易感性，表明抑制 Nogo-B 可能是治疗肝纤维化的一种方法。
