Effect of Creosote Bush-Derived NDGA on Expression of Genes Involved in Lipid Metabolism in Liver of High-Fructose Fed Rats: Relevance to NDGA Amelioration of Hypertriglyceridemia and Hepatic Steatosis.
Effect of Creosote Bush-Derived NDGA on Expression of Genes Involved in Lipid Metabolism in Liver of High-Fructose Fed Rats: Relevance to NDGA Amelioration of Hypertriglyceridemia and Hepatic Steatosis.
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DOI：
10.1371/journal.pone.0138203
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发表时间：
2015
期刊：
影响因子：
3.7
通讯作者：
Azhar S
中科院分区：
文献类型：
--
作者：
Zhang H;Li Y;Hu J;Shen WJ;Singh M;Hou X;Bittner A;Bittner S;Cortez Y;Tabassum J;Kraemer FB;Azhar S
北二氢愈木酸（NDGA）是木酚油灌木的主要代谢物，已被证明对代谢综合征（MetS）的核心成分有深远的影响，在几种血脂异常模型中降低血糖、游离脂肪酸（FFA）和甘油三酯（TG）水平，以及改善体重（肥胖）、胰岛素抵抗、糖尿病和高血压，并改善肝脂肪变性。本研究采用高果糖饮食（HFrD）喂养的高甘油三酯血症大鼠模型，进一步阐明NDGA发挥其抗高甘油三酯血症作用的潜在机制。在HFrD治疗组中，口服NDGA可降低血浆TG、葡萄糖、FFA和胰岛素水平，增加肝脏线粒体脂肪酸氧化，减轻肝脏TG积累。qRT-PCR检测表明，NDGA处理增加了关键脂肪酸转运（L-FABP、CD36）和脂肪酸氧化（ACOX1、CPT-2和PPARα转录因子）基因的mRNA表达，降低了脂肪生成相关酶（FASN、ACC1、SCD1、L-PK、ChREBP和SREBP-1c转录因子）的基因表达。Western blot分析表明，NDGA可上调肝脏胰岛素信号通路（P-Akt）、AMPK活性（P-AMPK）、MLYCD和PPARα蛋白水平，但可降低SCD1、ACC1和ACC2蛋白含量，并使ACC1活性失活（P-ACC1升高）。这些发现表明NDGA改善高甘油三酯血症和肝脂肪变性主要是通过干扰脂肪生成和促进脂肪酸氧化的增加通道。
Nordihydroguaiaretic acid (NDGA), the main metabolite of Creosote bush, has been shown to have profound effects on the core components of the metabolic syndrome (MetS), lowering blood glucose, free fatty acids (FFA) and triglyceride (TG) levels in several models of dyslipidemia, as well as improving body weight (obesity), insulin resistance, diabetes and hypertension, and ameliorating hepatic steatosis. In the present study, a high-fructose diet (HFrD) fed rat model of hypertriglyceridemia was employed to further delineate the underlying mechanism by which NDGA exerts its anti-hypertriglyceridemic action. In the HFrD treatment group, NDGA administration by oral gavage decreased plasma levels of TG, glucose, FFA, and insulin, increased hepatic mitochondrial fatty acid oxidation and attenuated hepatic TG accumulation. qRT-PCR measurements indicated that NDGA treatment increased the mRNA expression of key fatty acid transport (L-FABP, CD36), and fatty acid oxidation (ACOX1, CPT-2, and PPARα transcription factor) genes and decreased the gene expression of enzymes involved in lipogenesis (FASN, ACC1, SCD1, L-PK and ChREBP and SREBP-1c transcription factors). Western blot analysis indicated that NDGA administration upregulated hepatic insulin signaling (P-Akt), AMPK activity (P-AMPK), MLYCD, and PPARα protein levels, but decreased SCD1, ACC1 and ACC2 protein content and also inactivated ACC1 activity (increased P-ACC1). These findings suggest that NDGA ameliorates hypertriglyceridemia and hepatic steatosis primarily by interfering with lipogenesis and promoting increased channeling of fatty acids towards their oxidation.