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Polyphenol-rich foods as interventions for obesity and fatty liver disease.

机译：富含多酚的食物可作为肥胖症和脂肪肝疾病的干预措施。

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摘要

In the United States, approximately 68% of adults are overweight or obese, and this number is projected to rise to 86% by 2030. Obese individuals are at a greater risk for the development of several pathologies including diabetes, high blood pressure, cardiovascular disease, and some cancers. It is therefore imperative to investigate dietary interventions to combat obesity and its comorbidities. Obese individuals have been shown to be in a chronic state of inflammation due to increases in systemic endotoxin availability, a condition known as metabolic endotoxemia. Epidemiological evidence suggests that a high intake of plant-based foods rich in polyphenolic compounds is associated with decreased inflammation and a lower risk of chronic diseases. The overall goal of this project was to investigate the extent to which polyphenolic compounds and polyphenol-rich foods modulate markers of obesity and non-alcoholic fatty liver disease (NAFLD) in vitro and in vivo, and to explore the underlying mechanisms of action.;Previous studies have reported that tea polyphenols that contain one or more galloyl ester moieties and proanthocyanidins with a high degree of polymerization potently inhibit digestive enzymes including pancreatic lipase (PL) and phospholipase A2 (PLA2) in vitro. We investigated the importance of the position and number of galloyl groups in the PL inhibitory potency of tea polyphenols. We found that theaflavin-3,3?- digallate (TFdiG), theaflavin-3?-gallate (TF3'G), theaflavin-3-gallate (TF3G), theaflavin (TF), (-)-epigallocatechin-3-gallate (EGCG), (-)-epicatechin-3-gallate (ECG), and (-)- epigallocatechin (EGC) inhibited PL with 50% inhibition (IC50) of 1.9 microM, 4.2 microM, 3.0 microM, and 32.9 microM, 13.3 microM, 13.9 microM, and > 100 microM, respectively, confirming that the presence and indicating that the location of the galloyl ester moiety is essential for inhibitory potency. Using in silico modeling approaches, theaflavins were found to bind to Asn263 and Asp206 in PL. These amino acids form a pocket adjacent to the active site; galloyl-containing theaflavins were then able to form a hydrogen bond with His264, which forms part of the catalytic triad. This interaction is predicted to perturb the protonation status of His264 and reduce PL catalytic activity. The same mechanism of inhibition is seen with green tea catechins. I also observed that tea catechins inhibited PLA2 and this inhibition appears to be due to the catechins occupying a tunnel that leads to the active site. We also investigated the PL inhibitory activity of a panel of spices and berries, which have been reported by others to have high antioxidant activity. Of the extracts tested, cinnamon and cranberry extract (CBE) inhibited PL with the greatest potency, with IC50s of 10.03 microg/ml and 19.49 microg/ml, respectively. The total polyphenol content significantly inversely correlated with PL inhibitory potency for both spice (Pearson r = -0.90, p = 0.015) and berry extracts (Pearson r = -1.0, p = 0.001). These findings suggest a potential chemical basis for the inhibition of these two digestive enzymes by tea polyphenols and demonstrate potential beneficial inhibitory effects of berry and spice extracts on PL and PLA2.;NAFLD is a spectrum of diseases that ranges from simple steatosis to nonalcoholic steatohepatitis (NASH). NASH is an inflammatory disease that can eventually progress to cirrhosis. Polyphenols, such as those found in cranberries, have been shown to have antioxidant and anti-inflammatory properties. C57BL/6J mice were fed a 60%kcal from fat diet (HF). After 11 weeks, half of the mice were switched to HF diet supplemented with 0.8% CBE. After an additional 10 weeks of treatment, mice were euthanized and markers of obesity and NAFLD/NASH were examined. CBE supplementation had no effect on final weight gain, but it did significantly decrease total lipid area in the liver and plasma alanine aminotransferase levels compared to the HF toll-like receptor 4 gene expression (63%) and hepatic nuclear factor (NF)-kappaB gene expression (24%) compared to the HF group. Hepatic expression of tumor necrosis factor (TNF)-alpha, a pro-inflammatory cytokine gene regulated by NF-kappaB, and C-C chemokine receptor 2, a receptor for monocyte chemoattractant protein-1, were also significantly decreased by CBE supplementation compared to HF mice. In addition, CBE supplemented mice demonstrated reduced expression of nucleotide-binding domain, leucine-rich-containing family, pyrin domain-containing-3 inflammasome-related genes compared to HF-fed controls. Sirtuin-1 (Sirt1) gene expression was significantly increased by CBE supplementation, while Sirt1 target genes such as sterol response element-binding protein-1c, nuclear respiratory factor-1, and carnitine palmitoyl transferase 1? showed decreased expression compared to HF-fed mice. These data suggest that CBE may mitigate obesity-related hepatic inflammation and liver damage; however, additional experiments are needed to better understand the underlying mechanisms of action.
机译：在美国，大约68％的成年人超重或肥胖，到2030年，这一数字预计将上升到86％。肥胖的个体更容易患上多种疾病，包括糖尿病，高血压，心血管疾病和一些癌症。因此，必须研究饮食干预措施来对抗肥胖及其合并症。肥胖者由于全身性内毒素利用率的增加而处于慢性炎症状态，这种情况被称为代谢性内毒素血症。流行病学证据表明，富含多酚化合物的植物性食物摄入量高与炎症减少和慢性病风险降低有关。该项目的总体目标是研究多酚化合物和富含多酚的食物在体外和体内调节肥胖和非酒精性脂肪肝疾病（NAFLD）标记物的程度，并探讨其潜在的作用机制。以前的研究已经报道，含有一种或多种高聚合度的没食子酸酯部分和原花青素的茶多酚在体外能有效抑制消化酶，包括胰脂肪酶（PL）和磷脂酶A2（PLA2）。我们调查了茶多酚的PL抑制能力中没食子酰基基团的位置和数量的重要性。我们发现theaflavin-3,3α-gallate（TFdiG），theaflavin-3α-gallate（TF3'G），theaflavin-3-gallate（TF3G），theaflavin（TF），（-）-epigallocatechin-3-gallate （EGCG），（-）-表儿茶素-3-没食子酸酯（ECG）和（-）-表没食子儿茶素（EGC）抑制PL的50％抑制（IC50）分别为1.9 microM，4.2 microM，3.0 microM和32.9 microM，13.3 microM，13.9 microM和> 100 microM，分别证实了没食子酸酯部分的存在并表明其对抑制效能至关重要。使用计算机模拟方法，发现茶黄素与PL中的Asn263和Asp206结合。这些氨基酸在活性位点附近形成一个口袋。然后，含有没食子酰基的茶黄素能够与His264形成氢键，His264是催化三联体的一部分。预计这种相互作用会扰乱His264的质子化状态并降低PL催化活性。绿茶儿茶素具有相同的抑制机制。我还观察到茶儿茶素抑制了PLA2，这种抑制作用似乎是由于儿茶素占据了通向活性部位的通道。我们还研究了一组香料和浆果的PL抑制活性，其他人已经报道它们具有很高的抗氧化活性。在测试的提取物中，肉桂和酸果蔓提取物（CBE）抑制PL的效力最大，IC50分别为10.03 microg / ml和19.49 microg / ml。总多酚含量与香料（Pearson r = -0.90，p = 0.015）和浆果提取物（Pearson r = -1.0，p = 0.001）的PL抑制力呈显着负相关。这些发现为茶多酚抑制这两种消化酶提供了潜在的化学基础，并证明了浆果和香料提取物对PL和PLA2的潜在有益抑制作用.NAFLD是从简单脂肪变性到非酒精性脂肪性肝炎（ NASH）。 NASH是一种炎症性疾病，最终可以发展为肝硬化。多酚，例如蔓越莓中的多酚，已被证明具有抗氧化剂和抗炎特性。用脂肪饮食（HF）给C57BL / 6J小鼠饲喂60％大卡。 11周后，将一半的小鼠换成补充了0.8％CBE的HF饮食。再治疗10周后，对小鼠实施安乐死并检查肥胖和NAFLD / NASH标记物。补充CBE对最终体重增加没有影响，但与HF toll样受体4基因表达（63％）和肝核因子（NF）-kappaB相比，它确实显着降低了肝脏中总脂质面积和血浆丙氨酸氨基转移酶水平与HF组相比，其基因表达（24％）。与HF小鼠相比，补充CBE还显着降低了NF-κB调节的促炎细胞因子基因TNF-α和CC趋化因子受体2（单核细胞趋化蛋白1的受体）的肝表达。 。此外，与HF喂养的对照组相比，补充CBE的小鼠表现出核苷酸结合结构域，富含亮氨酸的家族，含吡喃结构域的3炎性体相关基因的表达降低。补充CBE可显着提高Sirtuin-1（Sirt1）基因的表达，而Sirt1靶基因如固醇反应元件结合蛋白1c，核呼吸因子1和肉碱棕榈酰转移酶1？与HF喂养的小鼠相比，显示出降低的表达。这些数据表明，CBE可能减轻与肥胖有关的肝炎和肝损害。但是，还需要进行其他实验才能更好地了解其潜在的作用机制。

著录项

  • 作者

    Glisan, Shannon Lee.;

  • 作者单位

    The Pennsylvania State University.;

  • 授予单位 The Pennsylvania State University.;
  • 学科 Food science.
  • 学位 Ph.D.
  • 年度 2016
  • 页码 214 p.
  • 总页数 214
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

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