The alleviating effect of sphingosine kinases 2 inhibitor K145 on nonalcoholic fatty liver
The alleviating effect of sphingosine kinases 2 inhibitor K145 on nonalcoholic fatty liver
复制标题
鞘氨醇激酶2抑制剂K145对非酒精性脂肪肝的缓解作用
DOI：
10.1016/j.bbrc.2021.09.060
复制
发表时间：
2021
期刊：
影响因子：
--
通讯作者：
Jihong Yuan
中科院分区：
文献类型：
--
作者：
Yanan Shi;Qing Wei;Yajin Liu;Jihong Yuan
鞘氨酸激酶2 （SphK2）抑制剂因其抗肿瘤作用而被开发用于肿瘤治疗。许多研究还探索了SphK2调节葡萄糖和脂质稳态，扩展了其在代谢性疾病治疗中的潜在功能。在这项研究中，我们发现腹腔注射K145显著减少了ob/ob小鼠的肝脏脂质积累，并恢复了肝功能。此外，接受K145治疗的db/db小鼠NALFD和高血糖均有改善。我们进一步分析了与脂质代谢相关的基因，发现脂肪生成基因FAS、ACC1和SREBP1c的表达显著降低，而线粒体脂肪酸b -氧化（FAO）相关基因CPT1A、MCAD、LCAD、PPAR- a、UCP2的表达升高。与体内研究一致，体外研究也证实了K145在降低人HL7702细胞脂质积累，同时抑制FAS、ACC1和SREBP1c mRNA表达的作用。提示K145改善肝脏脂质积累的可能机制部分是通过抑制脂肪生成。我们的研究表明，K145在NAFLD和糖尿病治疗药物开发中具有很好的作用。
Sphingosine kinase 2 (SphK2) inhibitors are developed for tumor therapy as considering its anti-tumor effect. Many studies also explored SphK2 modulated glucose and lipid homeostasis, which extended its potential function for metabolic diseases therapy. In this study, we discovered a significant reduction of hepatic lipid accumulation as well as recovery of liver function in ob/ob mice with intraperitoneal injection of K145. Also, db/db mice received K145 showed improvement of both NALFD and hyperglycemia. We furtherly analyzed the genes associated with lipid metabolism and found a remarkable decreased expression of lipogenic genes including FAS, ACC1 and SREBP1c whereas elevated mitochondrial fatty acid b -oxidation (FAO) related genes expression including CPT1A, MCAD, LCAD, PPAR- a , UCP2. Consistent to in vivo study, in vitro study also confirmed the role of K145 in decreasing lipid accumulation in human HL7702 cells, while inhibiting FAS, ACC1 and SREBP1c mRNA expression. It indicated a possible mechanism of K145 induced improvement of hepatic lipid accumulation partly via inhibition of lipigenesis. Our study suggested a promising role of K145 in drug development for NAFLD and diabetes therapy.