Galectin-12 modulates Kupffer cell polarization to alter the progression of nonalcoholic fatty liver disease

Abstract

Abstract 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.