The Mechanism of Cetp-Mediated Protection from High-Fat Diet-Induced Insulin Resistance

Cetp 介导的高脂饮食诱导胰岛素抵抗保护机制

• 批准号: 9125832
• 负责人: Brian T. Palmisano
• 金额: $ 4.86万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-01 至 2018-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9125832
• 关键词: Antisense Oligonucleotides; Area; Bile Acids; Bile fluid; Body Weight decreased; CETP gene; Cholesterol Esters; Clinical Management; Coronary heart disease; Data; Diabetes Mellitus; Diet; Down-Regulation; Dyslipidemias; Esters; Estrogen Receptor alpha; Estrogens; Euglycemic Clamping; Excision; Fatty acid glycerol esters; Female; Functional disorder; Gene Expression; Gene Targeting; Genes; Glucose Clamp; Goals; Health; Hepatic; High Density Lipoproteins; High Fat Diet; Human; Hyperglycemia; Hyperinsulinism; Hypertension; Insulin; Insulin Resistance; Insulin Signaling Pathway; Knock-out; Lipids; Lipoproteins; Liver; Mediating; Messenger RNA; Metabolic; Metabolic Diseases; Mouse Protein; Mus; Muscle; National Institute of Diabetes and Digestive and Kidney Diseases; Non-Insulin-Dependent Diabetes Mellitus; Obese Mice; Obesity; Ovarian hormone; Pathway interactions; Physicians; Physiological; Plasma; Process; Proteins; Risk; Role; Safe Sex; Scientist; Sex Characteristics; Signal Pathway; Signal Transduction; Signaling Molecule; Specificity; Techniques; Testing; Therapeutic; Training; Transgenic Mice; Transgenic Organisms; Triglycerides; United States; United States National Institutes of Health; Up-Regulation; Work; absorption; career; farnesoid X-activated receptor; feeding; glucose metabolism; glucose-6-phosphatase; improved; inhibitor/antagonist; insulin sensitivity; knock-down; male; metabolic abnormality assessment; new therapeutic target; novel; novel therapeutic intervention; premature; prevent; protein expression; protein function; protein transport; receptor; recombinase-mediated cassette exchange; reverse cholesterol transport; uptake

DESCRIPTION (provided by applicant): Obesity causes insulin resistance, which increases the risk of Type 2 Diabetes (T2D) and Coronary Heart Disease (CHD). Although weight loss is a primary goal in clinical management of obesity, long-term weight loss is rarely sustained. Therefore, it is imperative to understand pathways that might ameliorate the impact of obesity on T2D and CHD. We discovered that transgenic expression of Cholesteryl Ester Transfer Protein (Cetp) protects against high-fat diet (HFD)-induced insulin resistance in female mice in the setting of obesity. Cetp traffics triglyceride and cholesteryl ester (CE) between plasma lipoproteins, culminating in delivery of CE to the liver for secretion as bile - termed reverse cholesterol transport (RCT). Cetp inhibitors raise high- density lipoprotein (HDL) but fail to reduce risk for CHD, which may indicate that Cetp has non-HDL functions. Mice lack Cetp, so we used transgenic mice expressing Cetp to define how Cetp impacts insulin resistance. Using the hyperinsulinemic-euglycemic clamp technique, we found that Cetp protects against insulin resistance in females, but not males following 4 weeks of HFD. This protection was despite a similar degree of obesity. The objective of this proposal is to understand how Cetp protects against insulin resistance in diet-induced obese mice. Our discovery represents a novel and beneficial function of Cetp with regard to obesity pathophysiology. Despite high-fat feeding, Cetp expression preserved insulin signaling pathways in liver and muscle and insulin-mediated downregulation of mRNA for gluconeogenic genes Phosphoenopyruvate Carboxykinase (Pck1) and Glucose-6-Phosphatase (G6pc). We found that Cetp increased mRNA of the bile acid signaling molecule Small Heterodimer Partner (Shp) and increased estrogen signaling in liver. We hypothesize that Cetp promotes bile acid and estrogen signaling in liver to protect against diet-induced insulin resistance. Understanding how Cetp protects against diet-induced insulin resistance may yield novel therapeutic targets that lessen obesity's impact on CHD and T2D. In Aim 1, we will determine the mechanism of female-specificity in Cetp-mediated protection from HFD-induced insulin resistance. We expect that liver deletion of estrogen receptor alpha will diminish Cetp-mediated protection from HFD-induced insulin resistance. In Aim 2, we will determine the hepatic bile acid signaling pathways contributing to Cetp-mediated protection from HFD-induced insulin resistance. We expect that liver knockdown of Shp will abrogate Cetp- mediated protection from HFD-induced insulin resistance. Accomplishing the proposed work will 1) identify mechanisms responsible for sex differences that prevent metabolic disease and 2) identify liver bile acid signaling pathways downstream of Cetp that protect against diet-induced insulin resistance. Additionally, the work proposed in this application will support a critical nex step in my training as a physician-scientist whose career aims to make therapeutic connections between obesity and diabetes.

描述（由申请人提供）：肥胖会导致胰岛素抵抗，从而增加 2 型糖尿病 (T2D) 和冠心病 (CHD) 的风险。尽管减肥是肥胖临床治疗的主要目标，但长期减肥很少能持续。因此，必须了解可能改善肥胖对 T2D 和 CHD 影响的途径。我们发现，胆固醇酯转移蛋白 (Cetp) 的转基因表达可以防止肥胖雌性小鼠出现高脂饮食 (HFD) 诱导的胰岛素抵抗。 Cetp 在血浆脂蛋白之间运输甘油三酯和胆固醇酯 (CE)，最终将 CE 输送到肝脏以胆汁的形式分泌 - 称为反向胆固醇转运 (RCT)。 Cetp 抑制剂会升高高密度脂蛋白 (HDL)，但无法降低患 CHD 的风险，这可能表明 Cetp 具有非 HDL 功能。小鼠缺乏 Cetp，因此我们使用表达 Cetp 的转基因小鼠来确定 Cetp 如何影响胰岛素抵抗。使用高胰岛素-正常血糖钳夹技术，我们发现在 HFD 4 周后，Cetp 可以保护女性免受胰岛素抵抗，但不能保护男性。尽管肥胖程度相似，但仍能提供这种保护。该提案的目的是了解 Cetp 如何防止饮食诱导的肥胖小鼠产生胰岛素抵抗。我们的发现代表了 Cetp 在肥胖病理生理学方面的新颖且有益的功能。尽管进行高脂肪喂养，Cetp 表达仍保留了肝脏和肌肉中的胰岛素信号通路，以及胰岛素介导的糖异生基因磷酸烯丙酮酸羧激酶 (Pck1) 和葡萄糖 6-磷酸酶 (G6pc) mRNA 的下调。我们发现 Cetp 增加了胆汁酸信号分子小异二聚体伴侣 (Shp) 的 mRNA，并增加了肝脏中的雌激素信号传导。我们假设 Cetp 促进肝脏中的胆汁酸和雌激素信号传导，以防止饮食引起的胰岛素抵抗。了解 Cetp 如何预防饮食引起的胰岛素抵抗可能会产生新的治疗靶点，从而减轻肥胖对 CHD 和 T2D 的影响。在目标 1 中，我们将确定 Cetp 介导的针对 HFD 诱导的胰岛素抵抗的女性特异性机制。我们预计肝脏删除雌激素受体α将削弱Cetp介导的针对HFD诱导的胰岛素抵抗的保护作用。在目标 2 中，我们将确定肝胆汁酸信号通路有助于 Cetp 介导的 HFD 诱导的胰岛素抵抗保护。我们预计 Shp 的肝脏敲低将消除 Cetp 介导的针对 HFD 诱导的胰岛素抵抗的保护作用。完成拟议的工作将 1) 确定导致预防代谢疾病的性别差异的机制，2) 确定 Cetp 下游的肝胆汁酸信号通路，以防止饮食引起的胰岛素抵抗。此外，本申请中提出的工作将支持我作为一名医师科学家的培训中关键的下一步，我的职业目标是在肥胖和糖尿病之间建立治疗联系。