Therapeutic inhibition of miR-802 protects against obesity through AMPK-mediated regulation of hepatic lipid metabolism.
Therapeutic inhibition of miR-802 protects against obesity through AMPK-mediated regulation of hepatic lipid metabolism.
复制标题
miR-802 的治疗性抑制可通过 AMPK 介导的肝脏脂质代谢调节来预防肥胖。
作者：
Ni Y;Xu Z;Li C;Zhu Y;Liu R;Zhang F;Chang H;Li M;Sheng L;Li Z;Hou M;Chen L;You H;McManus DP;Hu W;Duan Y;Liu Y;Ji M
背景：宿主-寄生虫关系是基于寄生虫生存策略和宿主防御机制之间的微妙相互作用。众所周知，蠕虫感染困扰着全球超过10亿人，与肥胖患病率的下降有关。从宿主-寄生虫相互作用的角度剖析其潜在机制可以为治疗肥胖提供新的靶点。研究方法：C57 BL/6小鼠接受正常或高脂饮食（HFD），有或没有Sjp 40（一种主要成分的溶酶体衍生的可溶性卵抗原）处理。通过抑制剂抑制和慢病毒处理miR-802的功能丧失和获得实验来阐明miR-802/AMPK轴在宿主脂质代谢中的作用。肝细胞脂肪生成试验和代谢参数进行了评估，在体内和体外。通过pull-down、miRNA表达微阵列、定量RT-PCR、双荧光素酶报告基因分析和蛋白质印迹分析阐明了Sjp 40、CD 36、miR-802、Prkab 1和AMPK之间的潜在相互作用。结果：我们发现miR-802减少与日本血吸虫感染小鼠脂质代谢受损之间存在联系。减少的miR-802分别促进鼠Prkab 1或人Prkaa 1表达，这增加了磷酸化AMPK的水平，导致肝脏脂肪生成减少。此外，注射来自精子体的可溶性卵抗原（SEA）减弱代谢。我们证明，Sjp 40作为SEA的主要成分与肝细胞上的CD 36相互作用以抑制miR-802，导致AMPK通路的激活和随后的脂肪生成的减弱。总体而言：我们的研究揭示了miR-802/AMPK轴在肝脏脂质代谢中的重要作用，并确定了Sjp 40在治疗肥胖相关脂肪肝中的治疗潜力。
Background: The host-parasite relationship is based on subtle interplay between parasite survival strategies and host defense mechanisms. It is well known that helminth infection, which afflicts more than one billion people globally, correlates with a decreased prevalence of obesity. Dissecting the underlying mechanisms can provide new targets for treating obesity from the host-parasite interaction perspective. Methods: C57BL/6 mice received a normal or high-fat diet (HFD) with or without Sjp40 (one main component of schistosome-derived soluble egg antigens) treatment. Both the loss and gain-of-function experiments by the inhibitor suppression and lentivirus treatment of miR-802 were utilized to elucidate the role of miR-802/AMPK axis in host lipid metabolism. Hepatocyte lipogenesis assay and metabolic parameters were assessed both in vivo and in vitro. The potential interactions among Sjp40, CD36, miR-802, Prkab1, and AMPK were clarified by pull-down, miRNA expression microarray, quantitative RT-PCR, dual-luciferase reporter assay, and western blotting analysis. Results: We showed a link between decreased miR-802 and impaired lipid metabolism in Schistosoma japonicum infected mice. The decreased miR-802 promotes murine Prkab1 or human Prkaa1 expression, respectively, which increases levels of phosphorylated AMPK, resulting in a decrease in hepatic lipogenesis. Also, injection with schistosome-derived soluble egg antigens (SEA) attenuated metabolism. We demonstrated that Sjp40 as a main component of SEA interacted with CD36 on hepatocytes to inhibit miR-802, resulting in the activation of AMPK pathway and subsequent attenuation of lipogenesis. Collectively: Our study reveals the significant role of miR-802/AMPK axis in hepatic lipid metabolism and identifies the therapeutic potential of Sjp40 in treating obesity-related fatty liver.