Nordihydroguaiaretic acid protects against high-fat diet-induced fatty liver by activating AMP-activated protein kinase in obese mice
Nordihydroguaiaretic acid protects against high-fat diet-induced fatty liver by activating AMP-activated protein kinase in obese mice
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DOI：
10.1016/j.bbrc.2010.09.016
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发表时间：
2010-10-08
影响因子：
3.1
通讯作者：
Hwang, Jae-Kwan
中科院分区：
文献类型：
--
作者：
Lee, Myoung-Su;Kim, Daeyoung;Hwang, Jae-Kwan
非酒精性脂肪性肝病是慢性肝病最常见的原因之一，与代谢综合征密切相关。去甲二氢愈创木酸(NDGA)具有抑制脂蛋白脂酶的作用，但其对肝脂代谢的影响尚不清楚。我们评估了用NDGA处理的高脂饮食(HFD)喂养的C57BL/6J小鼠的体重、肥胖、肝脏组织学和肝脏甘油三酯含量。此外，我们还通过Western印迹和RT-PCR分析了NDGA对HepG2肝细胞的作用机制。NDGA(100或200 mg/kg/天)减少了饲喂高脂饲料8周的小鼠的体重增加、脂肪垫质量和肝脏甘油三酯的积聚，并改善了血脂参数。NDGA显著增加肝脏和HepG2肝细胞中AMP激活的蛋白激酶(AMPK)的磷酸化。NDGA下调成熟的SREBP-1及其靶基因(乙酰辅酶A羧基酶和脂肪酸合成酶)的水平，但上调与脂肪酸氧化有关的基因的表达，如过氧化物酶体增殖物激活受体(PPAR)α、PPARγ辅活化子-1、肉碱棕榈酰转移酶-1和解偶联蛋白-2。特异性AMPK抑制剂C可减弱NDGA对HepG2肝细胞脂代谢相关蛋白表达的影响。NDGA对HFD诱导的肝脏甘油三酯蓄积的有益影响是通过AMPK信号通路介导的，这表明NDGA是预防NAFLD的潜在靶点。(C)2010 Elsevier Inc.保留所有权利。
Nonalcoholic fatty liver disease, one of the most common causes of chronic liver disease, is strongly associated with metabolic syndrome. Nordihydroguaiaretic acid (NDGA) has been reported to inhibit lipoprotein lipase; however, the effect of NDGA on hepatic lipid metabolism remains unclear. We evaluated body weight, adiposity, liver histology, and hepatic triglyceride content in high-fat diet (HFD)-fed C57BL/6J mice treated with NDGA. In addition, we characterized the underlying mechanism of NDGA's effects in HepG2 hepatocytes by Western blot and RT-PCR analysis. NDGA (100 or 200 mg/kg/day) reduced weight gain, fat pad mass, and hepatic triglyceride accumulation, and improved serum lipid parameters in mice fed a HFD for 8 weeks. NDGA significantly increased AMP-activated protein kinase (AMPK) phosphorylation in the liver and in HepG2 hepatocytes. NDGA downregulated the level of mature SREBP-1 and its target genes (acetyl-CoA carboxylase and fatty acid synthase), but, it upregulated expression of genes involved in fatty acid oxidation, such as peroxisome proliferator-activated receptor (PPAR)alpha, PPAR gamma coactivator-1, carnitine palmitoyl transferase-1, and uncoupling protein-2. The specific AMPK inhibitor compound C attenuated the effects of NDGA on expression of lipid metabolism-related proteins in HepG2 hepatocytes. The beneficial effects of NDGA on HFD-induced hepatic triglyceride accumulation are mediated through AMPK signaling pathways, suggesting a potential target for preventing NAFLD. (C) 2010 Elsevier Inc. All rights reserved.