Department of Cell Metabolism and Nutrition, Graduate School of Medical Sciences, Kanazawa University, Kanazawa 920-8640, Ishikawa, Japan.
Jiangsu Carephar Pharmaceutical Co. Ltd., No.6 Xuzhuang Road, Xuanwu District, Nanjing 210014, Jiangsu, China.
Endocrinology. 2024 May 27;165(7). doi: 10.1210/endocr/bqae069.
The inhibition of hepatic macrophage and Kupfer cell recruitment and activation is a potential strategy for treating insulin resistance and nonalcoholic steatohepatitis (NASH). Cenicriviroc (CVC), a dual C-C chemokine receptor 2 (CCR2) and CCR5 antagonist, has shown antifibrotic activity in murine models of NASH and has been evaluated in clinical trials on patients with NASH. This study investigated the effects of CVC on macrophage infiltration and polarization in a lipotoxic model of NASH. C57BL/6 mice were fed a high-cholesterol, high-fat (CL) diet or a CL diet containing 0.015% CVC (CL + CVC) for 12 weeks. Macrophage recruitment and activation were assayed by immunohistochemistry and flow cytometry. CVC supplementation attenuated excessive hepatic lipid accumulation and peroxidation and alleviated glucose intolerance and hyperinsulinemia in the mice that were fed the CL diet. Flow cytometry analysis revealed that compared with the CL group, mice fed the CL + CVC diet had fewer M1-like macrophages, more M2-like macrophages, and fewer T cell counts, indicating that CVC caused an M2-dominant shift of macrophages in the liver. Similarly, CVC decreased lipopolysaccharide-stimulated M1-like macrophage activation, whereas it increased interleukin-4-induced M2-type macrophage polarization in vitro. In addition, CVC attenuated hepatic fibrosis by repressing hepatic stellate cell activation. Lastly, CVC reversed insulin resistance as well as steatosis, inflammation, and fibrosis of the liver in mice with pre-existing NASH. In conclusion, CVC prevented and reversed hepatic steatosis, insulin resistance, inflammation, and fibrogenesis in the liver of NASH mice via M2 macrophage polarization.
抑制肝巨噬细胞和库普弗细胞的募集和激活是治疗胰岛素抵抗和非酒精性脂肪性肝炎（NASH）的一种潜在策略。Cenicriviroc（CVC），一种双重 C-C 趋化因子受体 2（CCR2）和 CCR5 拮抗剂，在 NASH 的小鼠模型中显示出抗纤维化活性，并已在 NASH 患者的临床试验中进行了评估。本研究调查了 CVC 对 NASH 脂毒性模型中巨噬细胞浸润和极化的影响。C57BL/6 小鼠用高胆固醇、高脂肪（CL）饮食或含 0.015% CVC 的 CL 饮食（CL + CVC）喂养 12 周。通过免疫组织化学和流式细胞术检测巨噬细胞募集和激活。CVC 补充减轻了 CL 饮食喂养小鼠的肝脂质过度积累和过氧化，缓解了葡萄糖不耐受和高胰岛素血症。流式细胞术分析显示，与 CL 组相比，CL + CVC 饮食组小鼠的 M1 样巨噬细胞减少，M2 样巨噬细胞增多，T 细胞计数减少，表明 CVC 导致肝脏中巨噬细胞向 M2 型为主的转变。同样，CVC 降低了脂多糖刺激的 M1 样巨噬细胞活化，而增加了白细胞介素-4 诱导的 M2 型巨噬细胞极化。此外，CVC 通过抑制肝星状细胞激活来减轻肝纤维化。最后，CVC 逆转了具有预先存在 NASH 的小鼠的胰岛素抵抗以及肝脂肪变性、炎症和纤维化。总之，CVC 通过 M2 巨噬细胞极化来预防和逆转 NASH 小鼠的肝脂肪变性、胰岛素抵抗、炎症和纤维化。
