The Catholic University Liver Research Center, Department of Biomedicine & Health Sciences, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea.
Division of Gastroenterology and Hepatology, Department of Internal Medicine, College of Medicine, Uijeongbu St. Mary's Hospital, The Catholic University of Korea, Uijeongbu, Gyeonggi-do, Republic of Korea.
Front Immunol. 2024 Sep 23;15:1444100. doi: 10.3389/fimmu.2024.1444100. eCollection 2024.
Metabolic dysfunction-associated steatohepatitis (MASH) is characterized by persistent inflammatory cascades, with macrophage activation playing a pivotal role. Chitinase 1 (CHIT1), produced by activated macrophages, is a key player in this cascade. In this study, we aimed to explore the role of CHIT1 in MASH with progressive liver fibrosis.
Fibrotic liver tissue and serum from distinct patient groups were analyzed using nCounter MAX, flow cytometry, immunohistochemistry, and enzyme-linked immunosorbent assay. A MASH mouse model was constructed to evaluate the effectiveness of OATD-01, a chitinase inhibitor. Macrophage profiling was performed using single-nuclei RNA sequencing and flow cytometry.
CHIT1 expression in fibrotic liver tissues was significantly correlated with the extent of liver fibrosis, macrophages, and inflammation. Single-nuclei RNA sequencing demonstrated a notable increase in macrophages numbers, particularly of lipid-associated macrophages, in MASH mice. Treatment with OATD-01 reduced non-alcoholic fatty liver disease activity score and Sirius red-positive area. Additionally, OATD-01-treated mice had lower CHIT1, F4/80, and α-smooth muscle actin positivity, as well as significantly lower levels of inflammatory markers, pro-fibrotic genes, and matrix remodeling-related mRNAs than vehicle-treated mice. Although the population of F4/80CD11b intrahepatic mononuclear phagocytes remained unchanged, their infiltration and activation (CHIT1MerTK) significantly decreased in OATD-01-treated mice, compared with that observed in vehicle-treated mice.
Our study underscores the pivotal role of CHIT1 in MASH. The observed significant improvement in inflammation and hepatic fibrosis, particularly at higher doses of the CHIT1 inhibitor, strongly suggests the potential of CHIT1 as a therapeutic target in MASH accompanied by progressive liver fibrosis.
代谢相关脂肪性肝炎（MASH）的特征是持续的炎症级联反应，其中巨噬细胞激活起着关键作用。壳聚糖酶 1（CHIT1）由激活的巨噬细胞产生，是该级联反应中的关键分子。本研究旨在探讨 CHIT1 在伴有进行性肝纤维化的 MASH 中的作用。
使用 nCounter MAX、流式细胞术、免疫组织化学和酶联免疫吸附试验分析不同患者组的纤维化肝组织和血清。构建 MASH 小鼠模型，评估壳聚糖酶抑制剂 OATD-01 的疗效。使用单细胞 RNA 测序和流式细胞术进行巨噬细胞分析。
纤维化肝组织中 CHIT1 的表达与肝纤维化程度、巨噬细胞和炎症程度显著相关。单细胞 RNA 测序显示，MASH 小鼠的巨噬细胞数量明显增加，特别是脂质相关巨噬细胞。OATD-01 治疗可降低非酒精性脂肪性肝病活动评分和天狼星红阳性面积。此外，与 vehicle 治疗组相比，OATD-01 治疗组的 CHIT1、F4/80 和α-平滑肌肌动蛋白阳性率以及炎症标志物、促纤维化基因和基质重塑相关 mRNAs 的水平显著降低。虽然 F4/80CD11b 肝内单核吞噬细胞的群体没有改变，但 OATD-01 治疗组的浸润和激活（CHIT1MerTK）明显减少。
本研究强调了 CHIT1 在 MASH 中的关键作用。观察到炎症和肝纤维化的显著改善，特别是在更高剂量的 CHIT1 抑制剂时，强烈提示 CHIT1 作为伴有进行性肝纤维化的 MASH 的治疗靶点的潜力。
