Silencing of hepatic fatty acid transporter protein 5 in vivo reverses diet-induced non-alcoholic fatty liver disease and improves Hyperglycemia
Silencing of hepatic fatty acid transporter protein 5 in vivo reverses diet-induced non-alcoholic fatty liver disease and improves Hyperglycemia
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DOI：
10.1074/jbc.m803510200
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发表时间：
2008-08-08
影响因子：
4.8
通讯作者：
Stahl, Andreas
中科院分区：
文献类型：
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作者：
Doege, Holger;Grimm, Dirk;Stahl, Andreas
非酒精性脂肪肝是一种与肥胖和2型糖尿病相关的严重健康问题。为了研究肝脏脂肪酸摄取抑制的生物学结果和治疗潜力，我们利用腺相关病毒介导的RNA干扰技术，在小鼠非酒精性脂肪性肝病发生之前或之后，在体内敲低肝脏脂肪酸转运蛋白5的表达。使用这种方法，我们在这里展示了通过单次腺相关病毒注射实现小鼠肝脏中脂肪酸转运蛋白5特异性、无毒和持续敲除的能力，从而显著减少肝脏膳食脂肪酸摄取，减少热量摄取，并同时保护免受饮食诱导的非酒精性脂肪肝疾病的侵害。重要的是，脂肪酸转运蛋白5的敲低也能够逆转已经建立的非酒精性脂肪性肝病，从而显著改善全身葡萄糖稳态。因此，在高脂肪喂养期间，肝脏脂肪酸转运蛋白5的持续活性是维持热量摄取和脂肪酸进入肝脏所必需的，这可能为治疗非酒精性脂肪肝提供了一条新的途径。
Non-alcoholic fatty liver disease is a serious health problem linked to obesity and type 2 diabetes. To investigate the biological outcome and therapeutic potential of hepatic fatty acid uptake inhibition, we utilized an adeno-associated virus-mediated RNA interference technique to knock down the expression of hepatic fatty acid transport protein 5 in vivo prior to or after establishing non-alcoholic fatty liver disease in mice. Using this approach, we demonstrate here the ability to achieve specific, non-toxic, and persistent knockdown of fatty acid transport protein 5 in mouse livers from a single adeno-associated virus injection, resulting in a marked reduction of hepatic dietary fatty acid uptake, reduced caloric uptake, and concomitant protection from diet-induced non-alcoholic fatty liver disease. Importantly, knockdown of fatty acid transport protein 5 was also able to reverse already established non-alcoholic fatty liver disease, resulting in significantly improved whole-body glucose homeostasis. Thus, continued activity of hepatic fatty acid transport protein 5 is required to sustain caloric uptake and fatty acid flux into the liver during high fat feeding and may present a novel avenue for the treatment of non-alcoholic fatty liver disease.