Molecular impact of exercise training on regulation of hepatic fat and hepatic cholesterol metabolism with estrogens withdrawal

运动训练对雌激素戒断后肝脂肪和肝胆固醇代谢调节的分子影响

• 批准号: RGPIN-2014-06608
• 负责人: Lavoie, JeanMarc
• 金额: $ 2.19万
• 依托单位: Université de Montréal
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2018
• 资助国家: 加拿大
• 起止时间: 2018-01-01 至 2019-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=656814
• 关键词: Molecular; impact; exercise; training; regulation

OBJECTIVES: The overall goal of our research program for the next 5 years is to pursue our effort in understanding how exercise training mechanistically contributes to the proper regulation of liver lipid metabolism. In our proposed research program we will especially use the interactions known to occur between fat and cholesterol metabolism in liver and intestine to determine the action of physical training. To do that, animals will be submitted to different diets rich in lipids and/or cholesterol. These approaches will be carry on in ovariectomized (Ovx) and non-Ovx rats. Estrogens are known to have an important impact on liver fat metabolism. The use of this model is an important contribution to our understanding on how fat metabolism in link with cholesterol metabolism is regulated by the liver. Four research avenues will be investigated. ** 1) Under this arm of our next research program the hepatic LDL-receptor pathway including key related molecules (Pcsk9, SREBP-2, Lrp1) will be investigated in exercise trained Ovx animals fed with high fat (HF; 42% kcal) and/or high cholesterol (HChol; 0.25%) diets. The importance of this approach is based on the fact that 70% of all LDL-receptors are located in the liver.This approach is essential to understand how cholesterol under the present manipulations returns to liver and thus influence fat metabolism. This approach will be complemented by measurements of biliary metabolism, an important component of cholesterol metabolism in liver that has been shown to be associated with liver fat accumulation;** 2) In our second approach, VLDL production by the liver will be targeted. Basically we postulate that fat and cholesterol accumulation in liver of Ovx rats under HF/HChol diets is due to a decrease in VLDL production. To show that, we will directly measure VLDL production along with key molecular markers of VLDL synthesis (i.e. MTP, DGAT2 CideB).** 3) Ovx is paradoxically associated with an increase in nascent HDL and an increased hepatic influx of cholesterol from circulating HDL. In our next research program we intend to target key hepatic markers involved in HDL metabolism (SR-B1, ABCA1) and use our dietary approaches to better understand how the liver contributes to adaptations of HDL metabolism in link to estrogens withdrawal and exercise training. We postulate that HDL metabolism under the present situations adapts and even compensates for perturbations in LDL metabolism induced by changes in cholesterol availability in liver. ** 4) Approximately 40% of cholesterol reaching the liver comes from biliary acid re-absorption from intestine. In our next research program we intend to sample parts of intestine (duodenum, jejunum and ileum) to complement our experimental protocols by looking at nuclear receptors such as FXR and downstream genes (i.e. ASBT and OSTa/ß) that control biliary acids intestinal transport.** Novelty and expected significance: the novelty of our proposed research program is first to extend our knowledge of liver fat metabolism to liver cholesterol and biliary acid metabolism in link to two real life situations: postmenopausal women that constitute a large segment of the population, and exercise training an alternative to drugs therapies that represent an important socio-economic burden.

目标：我们未来 5 年研究计划的总体目标是努力了解运动训练如何从机制上促进肝脏脂质代谢的适当调节。在我们提出的研究计划中，我们将特别利用肝脏和肠道中脂肪和胆固醇代谢之间已知的相互作用来确定体育训练的作用。为此，动物将接受富含脂质和/或胆固醇的不同饮食。这些方法将在卵巢切除 (Ovx) 和非 Ovx 大鼠中进行。众所周知，雌激素对肝脏脂肪代谢有重要影响。该模型的使用对我们理解肝脏如何调节与胆固醇代谢相关的脂肪代谢做出了重要贡献。将调查四个研究途径。 ** 1) 在我们下一个研究计划的这一分支下，将在接受高脂肪（HF；42% kcal）和/或高胆固醇（HChol；0.25%）饮食喂养、经过运动训练的 Ovx 动物中研究包括关键相关分子（Pcsk9、SREBP-2、Lrp1）在内的肝脏 LDL 受体通路。这种方法的重要性在于，70% 的 LDL 受体位于肝脏。这种方法对于了解胆固醇在目前的操作下如何返回肝脏并从而影响脂肪代谢至关重要。这种方法将通过胆汁代谢的测量来补充，胆汁代谢是肝脏胆固醇代谢的重要组成部分，已被证明与肝脏脂肪积累有关；** 2) 在我们的第二种方法中，将针对肝脏产生的 VLDL。基本上，我们假设 HF/HChol 饮食下的 Ovx 大鼠肝脏中脂肪和胆固醇的积累是由于 VLDL 产生的减少。为了证明这一点，我们将直接测量 VLDL 的产生以及 VLDL 合成的关键分子标记（即 MTP、DGAT2 CideB）。** 3) Ovx 与新生 HDL 的增加和循环 HDL 中胆固醇流入肝脏的增加存在矛盾的相关性。在我们的下一个研究项目中，我们打算针对参与 HDL 代谢的关键肝脏标志物（SR-B1、ABCA1），并利用我们的饮食方法更好地了解肝脏如何促进与雌激素戒断和运动训练相关的 HDL 代谢适应。我们假设，在目前情况下，HDL 代谢会适应甚至补偿由肝脏中胆固醇可用性变化引起的 LDL 代谢扰动。 ** 4) 到达肝脏的胆固醇大约有 40% 来自肠道的胆汁酸重吸收。在我们的下一个研究计划中，我们打算对肠道部分（十二指肠、空肠和回肠）进行取样，通过观察控制胆汁酸肠道运输的 FXR 等核受体和下游基因（即 ASBT 和 OSTa/ß）来补充我们的实验方案。 ** 新颖性和预期意义：我们提出的研究计划的新颖性首先是将我们对肝脏脂肪代谢的知识扩展到肝脏 胆固醇和胆汁酸代谢与两种现实生活情况有关：占人口很大一部分的绝经后妇女，以及作为重要社会经济负担的药物治疗替代方案的运动训练。