Galectin-12 modulates Kupffer cell polarization to alter the progression of non-alcoholic fatty liver disease.

Non-alcoholic fatty liver disease (NAFLD) 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 (TGF)-β1, which contributes to liver fibrosis. Galectin-12 (Gal12) has been demonstrated to regulate lipid metabolism and macrophage polarization. The purpose of this study is to investigate the role of Gal12 in the development of NAFLD and fibrosis. Liver tissue from wild-type C57BL/6 mice fed with a high-fat diet containing cholesterol and cholic acid diet (HFCCD) for 4-12 weeks was used to examine Gal12 expression and its correlation with NAFLD. Furthermore, the effects of Gal12 on M2 macrophages during the progression of NAFLD was investigated by studying Kupffer cells from Gal12 knockout mice and doxycycline-inducible Gal12-/-THP-1 cells. Ablation of Gal12 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 IL-4, which was correlated with higher levels of TGF-β1. Moreover, Gal12-/- macrophage-conditioned medium promoted hepatic stellate cells (HSCs) myofibroblast differentiation, which was indicated by higher α-SMA expression levels compared to those treated with LacZ control medium. Finally, we demonstrated that Gal12 knockdown negatively regulated the suppressor of cytokine signaling 3 levels. These findings suggested that Gal12 balances M1/M2 polarization of Kupffer cells to prevent NAFLD progression.