Sphingosine 1-Phosphate Receptor Blockade Affects Pro-Inflammatory Bone Marrow-Derived Macrophages and Relieves Mouse Fatty Liver Injury.

ABSTRACT

Fatty liver injury is characterized by liver fat accumulation and results in serious health problems worldwide. There is no effective treatment that reverses fatty liver injury besides etiological therapy. Inflammation is an important macrophage-involving pathological process of liver injury. Here, we investigated the role of sphingosine 1-phosphate receptors (S1PRs) in fatty liver injury and explored whether S1PR2/3 blockade could cure fatty liver injury. A methionine-choline-deficient and a high-fat (MCDHF) diet was used to induce fatty liver injury, and the number of macrophages was evaluated by flow cytometry. Gene expressions were detected using RT-qPCR and cytometric bead array. In MCDHF-diet-fed mice, pro-inflammatory factor expressions were upregulated by fatty liver injury. The S1P level and S1PR2/3 expressions were significantly elevated. Moreover, increased S1P level and S1PR2/3 mRNA expressions were positively correlated with pro-inflammatory factor expressions in the liver. Furthermore, the number of pro-inflammatory macrophages (iMφ) increased in injured liver, and they were mainly bone-marrow-derived macrophages. In vivo, S1PR2/3 blockade decreased the amount of iMφ and inflammation and attenuated liver injury and fibrosis, although liver fat accumulation was unchanged. These data strongly suggest that anti-inflammatory treatment by blocking the S1P/S1PR2/3 axis attenuates fatty liver injury, which might serve as a potential target for fatty liver injury.