Therapeutic Inhibition of miR-33 Promotes Fatty Acid Oxidation but Does Not Ameliorate Metabolic Dysfunction in Diet-Induced Obesity.
Therapeutic Inhibition of miR-33 Promotes Fatty Acid Oxidation but Does Not Ameliorate Metabolic Dysfunction in Diet-Induced Obesity.
复制标题
DOI：
10.1161/atvbaha.115.306404
复制
发表时间：
2015-12
期刊：
影响因子：
--
通讯作者：
Rayner KJ
中科院分区：
文献类型：
--
作者：
Karunakaran D;Richards L;Geoffrion M;Barrette D;Gotfrit RJ;Harper ME;Rayner KJ
miR-33已成为脂质稳态的重要调节剂。抑制miR-33已被证明可预防动脉粥样硬化，然而，最近在小鼠中的研究表明，miR-33抑制可能对脂质和胰岛素代谢产生不利影响。考虑到miR-33抑制剂治疗动脉粥样硬化的治疗意义，我们试图测试在饮食诱导的肥胖小鼠模型中，以动脉粥样硬化保护剂量抑制miR-33是否会影响代谢参数。用10 mg/kg对照抗miR 33抑制剂或抗miR 33抑制剂治疗雄性小鼠20周并结合高脂肪饮食促进了所有组的等效体重增加。与对照抗miR相比，miR-33抑制剂增加了血浆总胆固醇并降低了血清甘油三酯，但与PBS处理的小鼠相比则没有。与对照相比，抗miR 33处理的小鼠中胰岛素抗性的降低没有改变，但是抗miR 33处理的小鼠中呼吸交换率（RER）降低。miR-33靶点Abca 1和Hadhb的肝脏表达在miR-33抑制后被去抑制。相反，在抗miR-33处理的小鼠中，推定的miR-33靶基因SREBP-1或其下游靶基因Fasn和Acc的蛋白水平没有改变，并且肝脏脂质蓄积在组间没有差异。在脂肪组织中，抗miR 33处理增加了Ampk基因表达和M2巨噬细胞极化的标志物。我们在饮食诱导的肥胖小鼠模型中证明，治疗性沉默miR-33可能促进全身氧化代谢，但不影响代谢失调。这表明，在已知可减少动脉粥样硬化的剂量下药理学抑制miR-33可能是一种安全的未来治疗方法。
miR-33 has emerged as an important regulator of lipid homeostasis. Inhibition of miR-33 has been demonstrated as protective against atherosclerosis, however, recent studies in mice suggest that miR-33 inhibition may have adverse effects on lipid and insulin metabolism. Given the therapeutic interest in miR-33 inhibitors for treating atherosclerosis, we sought to test whether pharmacologically inhibiting miR-33 at atheroprotective doses affected metabolic parameters in a mouse model of diet-induced obesity. Treatment of male mice with 10mg/kg control anti- or anti-miR33 inhibitors for 20 weeks in conjunction with high-fat diet promoted equivalent weight gain in all groups. miR-33 inhibitors increased plasma total cholesterol and decreased serum triglycerides compared to control anti-miR, but not compared to PBS treated mice. Metrics of insulin resistance were not altered in anti-miR33 treated mice compared to controls, however respiratory exchange ratio (RER) was decreased in anti-miR33 treated mice. Hepatic expression of miR-33 targets Abca1 and Hadhb were de-repressed upon miR-33 inhibition. In contrast, protein levels of putative miR-33 target gene SREBP-1 or its downstream targets genes Fasn and Acc were not altered in anti-miR33 treated mice, and hepatic lipid accumulation did not differ between groups. In the adipose tissue, anti-miR33 treatment increased Ampk gene expression and markers of M2 macrophage polarization. We demonstrate in a mouse model of diet-induced obesity that therapeutic silencing of miR-33 may promote whole-body oxidative metabolism but does not affect metabolic dysregulation. This suggests that pharmacological inhibition of miR-33 at doses known to reduce atherosclerosis may be a safe future therapeutic.