Department of Cell Metabolism and Nutrition, Graduate School of Medical Sciences, Kanazawa University, Kanazawa, Ishikawa 920-8640, Japan; School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou 325035, Zhejiang, China.
First Affiliated Hospital, Wenzhou Medical University, Wenzhou 325035, Zhejiang, China.
Metabolism. 2021 Dec;125:154914. doi: 10.1016/j.metabol.2021.154914. Epub 2021 Oct 14.
The global prevalence of nonalcoholic fatty liver disease (NAFLD) is increasing. Chemokines and their receptors have potential as therapeutic targets of NAFLD. We investigated the role of CC chemokine ligand 3 (CCL3) in the development of murine and human NAFLD.
CCL3-knockout mice (CCL3) and littermate CCL3 wild-type control mice (WT) were fed a high-cholesterol and high-fat (CL) diet for 16 weeks to induce NAFLD. We investigated the impact of CCL3 gene deletion in bone marrow cells and leptin-deficient ob/ob mice on CL diet-induced steatohepatitis. We assayed the serum CCL3 levels in 36 patients with biopsy-proven NAFLD and nine healthy control subjects.
Compared with normal chow (NC), the CL diet induced steatohepatitis and hepatic fibrosis and elevated the plasma CCL3 level. In the liver, CCL3 protein colocalized with F4/80 macrophages, especially CD11c M1-like macrophages, rather than other cell types. CCL3 attenuated CL diet-induced steatohepatitis and fibrosis associated with M2-dominant liver macrophages compared with the WT. The reconstitution of bone marrow (BM) cells from CCL3 attenuated steatohepatitis in WT mice fed a CL diet. Furthermore, crossing CCL3 onto the ob/ob background prevented CL diet-induced NAFLD in ob/ob mice, which was associated with a lesser inflammatory phenotype of liver macrophages. Also, the serum and hepatic levels of CCL3 were significantly increased in patients with non-alcoholic steatohepatitis (NASH) compared to those with simple fatty liver (NAFL) and healthy subjects.
Our data indicate that CCL3 facilitates macrophage infiltration into the liver and M1 polarization in the progression of steatohepatitis and highlight the need for further studies to determine the effect of CCL3-CCR1 and -CCR5 signaling blockade on the treatment of NAFLD.
非酒精性脂肪性肝病（NAFLD）的全球患病率正在上升。趋化因子及其受体具有成为 NAFLD 治疗靶点的潜力。我们研究了 CC 趋化因子配体 3（CCL3）在小鼠和人类 NAFLD 发展中的作用。
CCL3 基因敲除小鼠（CCL3）和同窝野生型对照小鼠（WT）喂食高胆固醇和高脂肪（CL）饮食 16 周，以诱导 NAFLD。我们研究了骨髓细胞中 CCL3 基因缺失和瘦素缺乏 ob/ob 小鼠对 CL 饮食诱导的脂肪性肝炎的影响。我们检测了 36 例经活检证实的 NAFLD 患者和 9 例健康对照者的血清 CCL3 水平。
与正常饲料（NC）相比，CL 饮食诱导了脂肪性肝炎和肝纤维化，并升高了血浆 CCL3 水平。在肝脏中，CCL3 蛋白与 F4/80 巨噬细胞，特别是 CD11c M1 样巨噬细胞，而不是其他细胞类型共定位。与 WT 相比，CCL3 减弱了 CL 饮食诱导的与 M2 优势肝巨噬细胞相关的脂肪性肝炎和纤维化。用 CCL3 转染 ob/ob 背景下的 CCL3 可预防 ob/ob 小鼠 CL 饮食诱导的 NAFLD，这与肝巨噬细胞的炎症表型减轻有关。此外，CCL3 在 ob/ob 小鼠中交叉也可防止 CL 饮食诱导的 NAFLD，这与肝巨噬细胞的炎症表型减轻有关。同样，与单纯性脂肪肝（NAFL）和健康受试者相比，非酒精性脂肪性肝炎（NASH）患者的血清和肝组织 CCL3 水平显著升高。
我们的数据表明，CCL3 促进了巨噬细胞浸润肝脏和 M1 极化在脂肪性肝炎的进展，并强调需要进一步研究以确定 CCL3-CCR1 和 -CCR5 信号阻断对 NAFLD 治疗的影响。
