Fluvastatin Sodium Ameliorates Obesity through Brown Fat Activation
Fluvastatin Sodium Ameliorates Obesity through Brown Fat Activation
复制标题
氟伐他汀钠通过激活棕色脂肪改善肥胖
DOI：
10.3390/ijms20071622
复制
发表时间：
2019
影响因子：
5.6
通讯作者：
Jin Wanzhu
中科院分区：
文献类型：
--
作者：
Yin Na;Zhang Hanlin;Ye Rongcai;Dong Meng;Lin Jun;Zhou Huiqiao;Huang Yuanyuan;Chen Li;Jiang Xiaoxiao;Nagaoka Kentaro;Zhang Chuanhai;Jin Wanzhu
棕色脂肪组织(BAT)是一种通过解偶联产热来燃烧能量的器官，是治疗肥胖症的有前途的靶点。然而，市场上仍然没有针对BAT的安全减肥药物。在本研究中，我们对食品和药物管理局(FDA)批准的636种化合物进行了大规模筛选，以寻找能够显著提高解偶联蛋白1(UCP1)mRNA表达的药物。在这些UCP1激活剂中，大多数是抗生素或致癌化合物。我们特别关注氟伐他汀钠(FS)，因为FS作为细胞羟甲基戊二酰辅酶A(HMG-CoA)还原酶的抑制剂，已经被批准用于治疗高胆固醇血症。我们发现，在细胞水平上，FS处理显著增加了人棕色脂肪细胞UCP1的表达和BAT活性。始终如一的是，FS治疗后氧化磷酸化相关基因的表达显著增加，成脂基因的表达没有差异。此外，FS治疗通过激活BAT对抗高脂饮食(HFD)诱导的小鼠体重增加。此外，给予FS显著增加能量消耗，改善血糖稳态，改善肝脏脂肪变性。此外，我们揭示了FS诱导皮下白色脂肪组织(SWAT)的褐化，这对能量代谢具有有益的影响。综上所述，我们的结果清楚地表明，FS作为一种有效的BAT激活剂，可能在治疗肥胖和相关代谢紊乱方面具有巨大的潜力。
Brown adipose tissue (BAT), an organ that burns energy through uncoupling thermogenesis, is a promising therapeutic target for obesity. However, there are still no safe anti-obesity drugs that target BAT in the market. In the current study, we performed large scale screening of 636 compounds which were approved by Food and Drug Administration (FDA) to find drugs that could significantly increase uncoupling protein 1 (UCP1) mRNA expression by real-time PCR. Among those UCP1 activators, most of them were antibiotics or carcinogenic compounds. We paid particular attention to fluvastatin sodium (FS), because as an inhibitor of the cellular hydroxymethyl glutaryl coenzyme A (HMG-CoA) reductase, FS has already been approved for treatment of hypercholesteremia. We found that in the cellular levels, FS treatment significantly increased UCP1 expression and BAT activity in human brown adipocytes. Consistently, the expression of oxidative phosphorylation-related genes was significantly increased upon FS treatment without differences in adipogenic gene expression. Furthermore, FS treatment resisted to high-fat diet (HFD)-induced body weight gain by activating BAT in the mice model. In addition, administration of FS significantly increased energy expenditure, improved glucose homeostasis and ameliorated hepatic steatosis. Furthermore, we reveal that FS induced browning in subcutaneous white adipose tissue (sWAT) known to have a beneficial effect on energy metabolism. Taken together, our results clearly demonstrate that as an effective BAT activator, FS may have great potential for treatment of obesity and related metabolic disorders.