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Avoiding toxicity associated with MTP ablation

避免与 MTP 消融相关的毒性

基本信息

批准号：
7792954
负责人：
M Mahmood Hussain
金额：
$ 39.65万
依托单位：
SUNY DOWNSTATE MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-02-01 至 2014-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7792954
关键词：
Ablation Accounting Adverse effects Advocate Agonist Alanine Transaminase Anabolism Apolipoproteins B Apoptosis Aspartate Transaminase Assimilations Atherosclerosis Canis familiaris Cardiovascular system Catabolism Cell Death Chemicals Cholesterol Cholesterol Esters Coronary Data Diabetes Mellitus Diet Disease Endoplasmic Reticulum Enzymes Event Excision Familial Combined Hyperlipidemia Familial Hypercholesterolemia Fatty Acids Fatty acid glycerol esters Future Gene Deletion Genes Genetic Golgi Apparatus Hepatic Hepatocyte Hyperlipidemia In Vitro Induction of Apoptosis Injury Intestines Lead Link Lipids Lipoproteins Liver Lovastatin MAPK8 gene Measurement Metabolic Metabolic Diseases Metabolic syndrome Microsomes Modality Molecular Molecular Chaperones Mus Obesity Olive oil preparation Operative Surgical Procedures Outcome Oxidoreductase Pathway interactions Patients Pharmaceutical Preparations Pharmacologic Substance Phospholipids Plasma Population Process Production Protein Inhibition Protein Isoforms Proteins Research Research Personnel Risk Factors Role Solutions Structural Protein Testing Thapsigargin Therapeutic Intervention Therapeutic Uses Toxic effect Transaminases Triglycerides Tunicamycin bariatric surgery base biological adaptation to stress caspase 12 cholesterol biosynthesis endoplasmic reticulum stress fatty acid oxidation feeding genetic inhibitor in vitro activity inhibitor/antagonist innovation liver transplantation microsomal triglyceride transfer protein novel novel strategies novel therapeutics public health relevance research study success

项目摘要

DESCRIPTION (provided by applicant): High plasma lipids and lipoproteins are risk factors for various cardiovascular and metabolic disorders. An approach to lower plasma lipids is to inhibit apoB-lipoprotein biosynthesis, a process critically dependent on an endoplasmic reticulum (ER) resident chaperone, microsomal triglyceride transfer protein (MTP). MTP inhibitors decrease apoB-lipoprotein secretion and lower plasma cholesterol. However, they increase plasma aminotransferases, such as ALT and AST, indicating liver injury. We hypothesize that increases in plasma hepatic enzymes associated with MTP inhibition are due to increases in microsomal free cholesterol, induction of ER stress and cell death. We further hypothesize that reducing cellular free cholesterol along with MTP inhibition might reduce hyperlipidemias and avoiding toxicities associated with MTP antagonists. In the first aim, Alb-Cre-MTPfl/fl or MTPfl/fl mice will be fed T-0901317, a LXR agonist to induce free cholesterol efflux; lovastatin, a HMG Co-A reductase antagonist to inhibit cellular cholesterol biosynthesis; or WY14643, a PPAR1 agonist to enhance 2-oxidation of fatty acids, for 3 or 24 weeks. In another group, &-3 fatty acids, PPAR1/4 agonists, will be injected intraperitoneally to reduce hepatic triglyceride and free cholesterol. In addition, Alb-Cre-MTPfl/fl mice will be fed a western diet and then treated with T-0901317, lovastatin, WY14643, or &-3 fatty acids. Experiments will then be performed in C57Bl/6J mice fed a western diet and fed daily with MTP inhibitors. Additionally, they will be fed olive oil alone or with other compounds described above to determine if toxicities associated with MTP inhibitors can be avoided by these treatments. Outcome measurements will involve changes in apoB-lipoproteins and hepatic enzymes in the plasma; hepatic triglycerides, esterified cholesterol, and free cholesterol; quantification of candidate mRNAs and proteins involved in cholesterol and triglyceride biosynthesis, ER stress, as well as AST/ALT isoforms. These studies will show that toxicities associated with MTP inhibition can be avoided by reducing hepatic free cholesterol. The second aim is to test the hypothesis that release of hepatic enzymes in the plasma is due to the induction of the ER stress and apoptosis. We will first demonstrate that MTP inhibition increases microsomal free cholesterol. Second, we will identify the ER stress pathways activated by MTP ablation/inhibition. Third, we will establish that MTP inhibition induces apoptosis. Fourth, a link between the ER stress and induction of apoptosis will be established. Fifth, importance of the ER stress pathways will be substantiated using ATF6-/-, CHOP-/- and Alb-Cre-Ire11fl/fl mice fed MTP inhibitors. Sixth, we will determine if induction of ER stress by tunicamycin increases plasma AST/ALT levels. At the completion of these studies, we will find out molecular mechanisms responsible for unwanted side effects associated with MTP therapy and suggest solutions to avoid these toxicities. These studies may lead to new therapeutic modalities for the treatment of various hyperlipidemias and have immediate potential for translational use. PUBLIC HEALTH RELEVANCE: This proposal is to find out why MTP drugs cause unwanted side effects and to come up with novel solutions to avoid these effects. These studies will explain molecular mechanisms involved in toxicities associated with MTP inhibitors and genetic ablations. Proposed studies may lead to new therapeutic modalities for the treatment of various disorders associated with high plasma lipids.

描述（由申请人提供）：高血浆脂质和脂蛋白是各种心血管和代谢疾病的危险因素。降低血浆脂质的一种方法是抑制 apoB 脂蛋白生物合成，该过程严重依赖于内质网 (ER) 常驻分子伴侣、微粒体甘油三酯转移蛋白 (MTP)。 MTP 抑制剂可减少 apoB 脂蛋白的分泌并降低血浆胆固醇。然而，它们会增加血浆转氨酶，例如 ALT 和 AST，表明存在肝损伤。我们假设与 MTP 抑制相关的血浆肝酶增加是由于微粒体游离胆固醇增加、ER 应激和细胞死亡的诱导。我们进一步假设减少细胞游离胆固醇并抑制 MTP 可能会降低高脂血症并避免与 MTP 拮抗剂相关的毒性。在第一个目标中，Alb-Cre-MTPfl/fl 或 MTPfl/fl 小鼠将被喂食 T-0901317，一种 LXR 激动剂，以诱导游离胆固醇流出；洛伐他汀，一种 HMG Co-A 还原酶拮抗剂，可抑制细胞胆固醇生物合成；或 WY14643，一种 PPAR1 激动剂，可增强脂肪酸 2-氧化，持续 3 或 24 周。在另一组中，腹膜内注射α-3脂肪酸、PPAR1/4激动剂，以降低肝甘油三酯和游离胆固醇。此外，Alb-Cre-MTPfl/fl小鼠将被喂食西方饮食，然后用T-0901317、洛伐他汀、WY14643或&-3脂肪酸治疗。然后将在采用西方饮食并每天喂食 MTP 抑制剂的 C57Bl/6J 小鼠中进行实验。此外，他们将单独喂食橄榄油或与上述其他化合物一起喂食，以确定这些治疗是否可以避免与 MTP 抑制剂相关的毒性。结果测量将涉及血浆中apoB脂蛋白和肝酶的变化；肝甘油三酯、酯化胆固醇和游离胆固醇；量化参与胆固醇和甘油三酯生物合成、ER 应激以及 AST/ALT 亚型的候选 mRNA 和蛋白质。这些研究将表明，通过降低肝游离胆固醇可以避免与 MTP 抑制相关的毒性。第二个目的是检验血浆中肝酶的释放是由于内质网应激和细胞凋亡的诱导所致的假设。我们将首先证明 MTP 抑制会增加微粒体游离胆固醇。其次，我们将确定 MTP 消融/抑制激活的 ER 应激途径。第三，我们将确定 MTP 抑制诱导细胞凋亡。第四，将建立内质网应激和细胞凋亡诱导之间的联系。第五，使用 MTP 抑制剂喂养的 ATF6-/-、CHOP-/- 和 Alb-Cre-Ire11fl/fl 小鼠将证实 ER 应激途径的重要性。第六，我们将确定衣霉素诱导 ER 应激是否会增加血浆 AST/ALT 水平。这些研究完成后，我们将找出导致 MTP 治疗相关不良副作用的分子机制，并提出避免这些毒性的解决方案。这些研究可能会带来治疗各种高脂血症的新治疗方式，并具有直接的转化应用潜力。公共健康相关性：该提案旨在找出 MTP 药物引起不良副作用的原因，并提出新的解决方案来避免这些影响。这些研究将解释与 MTP 抑制剂和基因消融相关的毒性的分子机制。拟议的研究可能会导致治疗与高血脂相关的各种疾病的新治疗方式。