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首页> 外文学位 >The molecular mechanistic effects of a grape seed procyanidin extract in regulating hepatic lipid metabolism.
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The molecular mechanistic effects of a grape seed procyanidin extract in regulating hepatic lipid metabolism.

机译：葡萄籽原花青素提取物在调节肝脂质代谢中的分子机制作用。

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摘要

Hypertriglyceridemia is an independent risk factor for cardiovascular disease (CVD), the leading cause of mortality in the United States. Previous studies have shown that a grape seed procyanidin extract (GSPE) exerts potent triglyceride-lowering effects in normolipidemic rodents through acting as a co-agonist ligand for the farnesoid x receptor (Fxr), repressing lipogenesis while also increasing bile acid (BA) and subsequent cholesterol synthesis. The aim of the studies presented herein was to elucidate the underlying molecular mechanisms responsible for these physiological effects in both normolipidemic and hyperlipidemic states.;Along with the Fxr-dependent mechanism described above, previous studies have shown increased Cpt1a and Apoa5 gene expression following GSPE treatment, suggesting increased fatty acid catabolism. Because histone deacetylaces (HDACs) exert epigenetic control on fatty acid catabolism and dietary flavonoids have proven to be effective HDAC inhibitors, we assessed whether GSPE increases fatty acid catabolism and lowers serum triglyceride (TG) levels via HDAC inhibition and subsequent modulation of Pparalpha phosphorylation and target gene expression. Studies were carried out in liver tissue from normolipidemic male C57BL/6 mice administered 250 mg/kg GSPE for 14 hours. We found that GSPE treatment led to inhibition of HDAC2 and 3 activity and increased histone acetylation. Pparalpha gene expression was increased, and although Pparalpha protein expression was decreased, phosphorylated Pparalpha protein levels were increased over two-fold, while expression of Pparalpha target-genes involved in fatty acid catabolism were also up-regulated. Additionally, expression of Fgf21, a hormone and Pparalpha target, demonstrated an eight-fold increase in gene expression, while serum levels were increased seven-fold. Such changes in gene and protein expression were accompanied by a 28% decrease in serum TG levels. Collectively these results suggest, for the first time, that GSPE may lower serum TG via HDAC inhibition, a process that allows increased phosphorylation of Pparalpha, resulting in increased fatty acid catabolism.;Because hypertriglyceridemia is causally associated with CVD, we next assessed the hypolipidemic effects of GSPE on fructose-induced dyslipidemia. Prior to GSPE treatment, rats were fed either a high-fructose diet, which elevated serum TG and liver fat accumulation, or a standard chow control diet. Following the initial 8-week period of fructose feeding, rats continued on their respective diets while also receiving either GSPE (250 mg/kg) or vehicle (water) for 7 days. Rats administered GSPE on the high fructose diet showed a 41% decrease in serum TG levels compared to rats administered vehicle on the high fructose diet, as well as increased fecal cholesterol excretion. GSPE treatment in the presence of fructose repressed the expression of key genes involved in TG synthesis, including sterol regulatory element binding protein 1c (Srebp-1c), while robustly increasing the expression of genes involved in cholesterol synthesis, particularly the rate-limiting enzyme 3-hydroxy-3-methylglutaryl-CoA reductase (Hmgcr). Expression of genes involved in BA and cholesteryl ester synthesis and export were not increased. Such results indicate that, in the presence of dietary fructose, GSPE diverts lipogenic substrates into cholesterol synthesis in order to maintain hepatic lipid homeostasis, subsequently secreting the cholesterol via a non-biliary route into the plasma, where it is ultimately sent to the intestine for excretion via trans-intestinal cholesterol excretion (TICE). Because excessive fructose intake has been causally linked with the CVD risk factors hypertriglyceridemia and fatty liver, these results suggest that GSPE treatment may be beneficial in mitigating the negative metabolic effects induced by a high fructose diet.;In conclusion, the results presented in this thesis suggest that GSPE lowers serum TG in vivo through multiple mechanisms, including epigenetic regulation via modulation of HDAC and Pparalpha activity and also via modulation of cholesterol synthesis and excretion, depending on the physiological state. Because HDAC inhibitors are gaining recognition as hypolipidemic agents and GSPE effectively lowers serum TG in a hyperlipidemic state, further studies are warranted to assess the therapeutic effects of this natural product in treating CVD-associated risk factors.
机译：高甘油三酯血症是心血管疾病（CVD）的独立危险因素，而心血管疾病是美国死亡的主要原因。先前的研究表明，葡萄籽原花青素提取物（GSPE）通过充当法呢类x受体（Fxr）的辅助激动剂配体，抑制脂肪生成，同时增加胆汁酸（BA）和血脂，从而在降血脂啮齿动物中发挥有效的降甘油三酸酯作用。随后的胆固醇合成。本文介绍的研究目的是阐明在正常血脂和高血脂状态下导致这些生理效应的潜在分子机制。除了上述的Fxr依赖性机制外，先前的研究还显示GSPE处理后Cpt1a和Apoa5基因表达增加，提示脂肪酸分解代谢增加。由于组蛋白脱乙酰基（HDACs）对脂肪酸分解代谢发挥表观遗传控制作用，并且饮食中的黄酮类化合物已被证明是有效的HDAC抑制剂，因此我们评估了GSPE是否通过HDAC抑制和随后对Pparalpha磷酸化的调节而增加了脂肪酸分解代谢并降低了血清甘油三酸酯（TG）的水平。靶基因表达。在给予250 mg / kg GSPE的降血脂雄性C57BL / 6小鼠的肝组织中进行了14小时的研究。我们发现GSPE处理导致抑制HDAC2和3活性并增加组蛋白乙酰化。 Pparalpha基因表达增加，虽然Pparalpha蛋白表达减少，但磷酸化的Pparalpha蛋白水平增加了两倍，而参与脂肪酸分解代谢的Pparalpha目标基因的表达也被上调。此外，激素和Pparalpha靶标Fgf21的表达证明基因表达增加了八倍，而血清水平却增加了七倍。基因和蛋白质表达的这种变化伴随着血清TG水平降低28％。总的来说，这些结果首次表明，GSPE可能通过抑制HDAC降低了血清TG，这一过程使Pparalpha的磷酸化增加，导致脂肪酸分解代谢增加。；由于高甘油三酯血症与CVD有因果关系，我们接下来评估了降血脂GSPE对果糖致血脂异常的影响。在GSPE治疗之前，给大鼠喂食高果糖饮食（可增加血清TG和肝脂肪蓄积）或标准饮食控制饮食。在最初的8周果糖喂养期后，大鼠继续各自的饮食，同时还接受GSPE（250 mg / kg）或赋形剂（水）持续7天。与高果糖饮食媒介物相比，高果糖饮食媒介物GSPE的大鼠血清TG降低41％，粪便胆固醇排泄增加。在果糖存在下的GSPE处理抑制了TG合成中涉及的关键基因的表达，包括固醇调节元件结合蛋白1c（Srebp-1c），同时强烈增加了胆固醇合成中涉及的基因的表达，特别是限速酶3 -羟基-3-甲基戊二酰辅酶A还原酶（Hmgcr）。参与BA和胆固醇酯合成和输出的基因的表达没有增加。这些结果表明，在饮食中存在果糖的情况下，GSPE会将脂肪形成底物转移到胆固醇合成中，以维持肝脂质稳态，随后通过非胆汁途径将胆固醇分泌到血浆中，最终将其送至肠道进行治疗。通过肠内胆固醇排泄（TICE）排泄。由于果糖摄入过多与CVD危险因素高甘油三酯血症和脂肪肝有因果关系，因此这些结果表明GSPE治疗可能有助于减轻高果糖饮食引起的负面代谢影响。提示GSPE通过多种机制降低体内血清TG，包括通过调节HDAC和Pparalpha活性进行表观遗传调控，以及通过调节胆固醇的合成和排泄，具体取决于生理状态。由于HDAC抑制剂已被公认是降血脂药，而GSPE可有效降低高血脂状态下的血清TG，因此有必要进行进一步的研究以评估这种天然产物在治疗与CVD相关的危险因素中的治疗作用。

著录项

  • 作者

    Downing, Laura E.;

  • 作者单位

    University of Nevada, Reno.;

  • 授予单位 University of Nevada, Reno.;
  • 学科 Molecular biology.;Nutrition.;Biochemistry.
  • 学位 M.S.
  • 年度 2016
  • 页码 161 p.
  • 总页数 161
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

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