Mauer Amy S, Hirsova Petra, Maiers Jessica L, Shah Vijay H, Malhi Harmeet
Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota.
Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota
Am J Physiol Gastrointest Liver Physiol. 2017 Mar 1;312(3):G300-G313. doi: 10.1152/ajpgi.00222.2016. Epub 2016 Dec 30.
Nonalcoholic steatohepatitis (NASH) is a lipotoxic disorder, wherein proinflammatory lipids, such as ceramide and its derivative sphingosine 1-phosphate (S1P), contribute to macrophage-associated liver inflammation. For example, we have previously demonstrated a role for S1P in steatotic hepatocyte-derived S1P-enriched extracellular vesicles in macrophage chemotaxis in vitro. Therefore, we hypothesized that FTY720, an S1P antagonist, would ameliorate NASH by inhibiting proinflammatory monocyte chemotaxis. To test our hypothesis, NASH was established in C57BL/6 male mice by feeding a diet high in fructose, saturated fat, and cholesterol for 22 wk. Then mice received daily intraperitoneal injections of FTY720 for 2 wk before analysis of liver injury, inflammation, and fibrosis. FTY720-treated mice with NASH demonstrated improved liver histology with a significant reduction in hepatocyte ballooning and inflammatory foci. Hepatomegaly was reversed, and liver triglycerides were reduced following FTY720 administration to mice with NASH. Correspondingly, serum ALT levels, hepatic inflammatory macrophage accumulation, and the expression of Ly6C in recruited myeloid cells was reduced in FTY720-treated mice. Hepatic collagen accumulation and expression of α-smooth muscle actin were significantly lowered as well. Body composition, energy consumption and utilization, and hepatic sphingolipid composition remained unchanged following FTY720 administration. FTY720 ameliorates murine nonalcoholic steatohepatitis. Reduction in liver injury and inflammation is associated with a reduction in hepatic macrophage accumulation, likely due to dampened recruitment of circulating myeloid cells into the liver. Nonalcoholic steatohepatitis may be a novel indication for the therapeutic use of FTY720. There are no approved pharmacologic therapies for nonalcoholic steatohepatitis (NASH), the leading cause of chronic liver disease worldwide. This study describes the use of FTY720, a novel small molecule, for the amelioration of NASH in a mouse model. We demonstrate that 2-wk administration of FTY720 to mice with NASH led to a reduction in liver injury, inflammation, and fibrosis. These data provide a preclinical rationale for studying this drug in human NASH.
非酒精性脂肪性肝炎（NASH）是一种脂毒性疾病，其中促炎脂质，如神经酰胺及其衍生物鞘氨醇1-磷酸（S1P），会导致巨噬细胞相关的肝脏炎症。例如，我们之前已经证明S1P在体外脂肪变性肝细胞衍生的富含S1P的细胞外囊泡对巨噬细胞趋化作用中发挥作用。因此，我们假设S1P拮抗剂FTY720通过抑制促炎单核细胞趋化作用来改善NASH。为了验证我们的假设，通过给C57BL/6雄性小鼠喂食高果糖、饱和脂肪和胆固醇的饮食22周来建立NASH模型。然后在分析肝损伤、炎症和纤维化之前，小鼠每天腹腔注射FTY720，持续2周。接受FTY720治疗的患有NASH的小鼠肝脏组织学得到改善，肝细胞气球样变和炎症灶显著减少。肝肿大得到逆转，给患有NASH的小鼠施用FTY720后肝脏甘油三酯减少。相应地，在接受FTY720治疗的小鼠中，血清谷丙转氨酶（ALT）水平、肝脏炎性巨噬细胞积累以及募集的髓样细胞中Ly6C的表达均降低。肝脏胶原积累和α-平滑肌肌动蛋白的表达也显著降低。施用FTY720后，身体组成、能量消耗和利用以及肝脏鞘脂组成保持不变。FTY720可改善小鼠非酒精性脂肪性肝炎。肝损伤和炎症的减轻与肝脏巨噬细胞积累的减少有关，这可能是由于循环髓样细胞向肝脏的募集减少所致。非酒精性脂肪性肝炎可能是FTY720治疗应用的一个新适应症。对于非酒精性脂肪性肝炎（NASH），全球慢性肝病的主要原因，目前尚无批准的药物治疗方法。本研究描述了新型小分子FTY720在小鼠模型中改善NASH的应用。我们证明，给患有NASH的小鼠施用2周的FTY720可导致肝损伤、炎症和纤维化减轻。这些数据为在人类NASH中研究这种药物提供了临床前理论依据。
