Department of Biomedical Engineering and Environmental Sciences, National Tsing Hua University, Hsinchu 300, Taiwan.
Department of Emergency Medicine, Taichung Tzu Chi Hospital, Taichung 427, Taiwan.
Glycobiology. 2023 Oct 6;33(8):673-682. doi: 10.1093/glycob/cwad062.
Nonalcoholic fatty liver disease is caused by an imbalance in lipid metabolism and immune response to pose a risk factor for liver fibrosis. Recent evidence indicates that M2 macrophages secrete transforming growth factor-β1, which contributes to liver fibrosis. Galectin-12 has been demonstrated to regulate lipid metabolism and macrophage polarization. The purpose of this study is to investigate the role of galectin-12 in the development of nonalcoholic fatty liver disease and fibrosis. Liver tissue from wild-type C57BL/6 mice fed with a high-fat diet containing cholesterol and cholic acid for 4-12 weeks was used to examine galectin-12 expression and its correlation with nonalcoholic fatty liver disease. Furthermore, the effects of galectin-12 on M2 macrophages during the progression of nonalcoholic fatty liver disease were investigated by studying Kupffer cells from galectin-12 knockout mice and doxycycline-inducible Gal12-/-THP-1 cells. Ablation of galectin-12 promoted M2 polarization of Kupffer cells, as indicated by higher levels of M2 markers, such as arginase I and chitinase 3-like protein 3. Furthermore, the activation of signal transducer and activator of transcription 6 was significantly higher in Gal12-/- macrophages activated by interleukin-4, which was correlated with higher levels of transforming growth factor-β1. Moreover, Gal12-/- macrophage-conditioned medium promoted hepatic stellate cells myofibroblast differentiation, which was indicated by higher α-smooth muscle actin expression levels compared with those treated with LacZ control medium. Finally, we demonstrated that galectin-12 knockdown negatively regulated the suppressor of cytokine signaling 3 levels. These findings suggested that galectin-12 balances M1/M2 polarization of Kupffer cells to prevent nonalcoholic fatty liver disease progression.
非酒精性脂肪性肝病是由脂质代谢失衡和免疫反应引起的，是肝纤维化的一个危险因素。最近的证据表明，M2 巨噬细胞分泌转化生长因子-β1，导致肝纤维化。半乳糖凝集素-12 已被证明可调节脂质代谢和巨噬细胞极化。本研究旨在探讨半乳糖凝集素-12在非酒精性脂肪性肝病和纤维化发展中的作用。使用野生型 C57BL/6 小鼠的肝组织，这些小鼠在含有胆固醇和胆酸的高脂肪饮食中喂养 4-12 周，以检查半乳糖凝集素-12 的表达及其与非酒精性脂肪性肝病的相关性。此外，通过研究半乳糖凝集素-12 敲除小鼠的枯否细胞和强力霉素诱导的 Gal12-/-THP-1 细胞，研究了半乳糖凝集素-12 在非酒精性脂肪性肝病进展过程中对半乳糖凝集素-12 对 M2 巨噬细胞的影响。半乳糖凝集素-12 的缺失促进了枯否细胞的 M2 极化，这表现为 M2 标志物（如精氨酸酶 I 和几丁质酶 3 样蛋白 3）水平升高。此外，在白细胞介素-4 激活的 Gal12-/-巨噬细胞中，信号转导和转录激活因子 6 的激活显著升高，这与转化生长因子-β1 水平升高有关。此外，Gal12-/-巨噬细胞条件培养基促进肝星状细胞肌成纤维细胞分化，与用 LacZ 对照培养基处理的细胞相比，α-平滑肌肌动蛋白表达水平更高。最后，我们证明半乳糖凝集素-12 敲低可负调控细胞因子信号转导抑制因子 3 水平。这些发现表明，半乳糖凝集素-12 平衡枯否细胞的 M1/M2 极化，以防止非酒精性脂肪性肝病的进展。
