Transplantation of brown adipose tissue up-regulates miR-99a to ameliorate liver metabolic disorders in diabetic mice by targeting NOX4
Transplantation of brown adipose tissue up-regulates miR-99a to ameliorate liver metabolic disorders in diabetic mice by targeting NOX4
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DOI：
10.1080/21623945.2020.1721970
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发表时间：
2020-01-01
期刊：
影响因子：
3.3
通讯作者：
Guan, Meiping
中科院分区：
文献类型：
--
作者：
Li, Ping;Fan, Cunxia;Guan, Meiping
非酒精性脂肪性肝病（NAFLD）是肝脏损害的主要原因，与糖尿病有着千丝万缕的联系。然而，目前还没有具体的手段来改善糖尿病患者脂肪肝的病理。棕色脂肪组织（BAT）是重要的内分泌器官，分泌脂肪因子和参与全身代谢调节的microRNA（miRNAs）。为探讨BAT移植对糖尿病小鼠肝脏脂质代谢的影响，将雄性供体小鼠BAT移植到链脲佐菌素（STZ）联合高脂饮食（HFD）诱导的糖尿病小鼠体内。移植后10周，BAT移植显著降低糖尿病小鼠血糖和血脂，下调FAS、CD36、Scd1、ACC α、NOX 2、NOX 4、TGF-β 1、FN和COL-1，上调Nrf2，逆转肝脏病理改变，增加循环miR-99a。为了验证循环miR-99a是否通过靶向抑制N0X4来改善氧化应激，我们使用0.4mM棕榈酸（PA）处理L02细胞。转染miR-99a模拟物后，NOX4蛋白表达明显降低，转染miR-99a抑制剂后，NOX4蛋白表达明显升高。荧光素酶报告基因检测证实miR-99a可靶向NOX4 mRNA。这些发现阐明了miR-99a和NOX 4在BAT移植对糖尿病小鼠肝脏有益作用中的作用。
Nonalcoholic fatty liver disease (NAFLD), main cause of liver damage, is inextricably linked to diabetes. However, there is no specific means to improve the pathology of fatty liver in diabetic patients. Brown adipose tissue (BAT) is an important endocrine organ that secretes adipokines and microRNAs (miRNAs) involved in systemic metabolic regulation. To investigate the effects of BAT transplantation on liver lipid metabolism in diabetic mice, we transplanted BAT from male donor mice into diabetic mice induced by streptozotocin (STZ) combined with high-fat diet (HFD). At 10 weeks after transplantation, BAT transplantation significantly decreased the blood glucose and lipid, downregulated FAS, CD36, Scd1, ACC alpha, NOX2, NOX4, TGF-beta 1, FN and COL-1, up-regulated Nrf2, reversed the pathological changes of liver and increased the circulating miR-99a in diabetic mice. To verify whether circulating miR-99a improves oxidative stress by targeting inhibition of NOX4, we used 0.4mM palmitic acid (PA) to treat the LO2 cells. The expression of NOX4 protein was significantly decreased after transfection with miR-99a mimic, and increased after transfection with miR-99a inhibitor. Luciferase reporter assay confirmed that miR-99a could target NOX4 mRNA. These findings clarify the role of miR-99a and NOX4 in liver beneficial effect of BAT transplantation in diabetic mice.