Molecular Mechanism of Protein Kinase Cbeta-Mediated Cholesterol Homeostasis

蛋白激酶Cbeta介导的胆固醇稳态的分子机制

基本信息

批准号：
7653553
负责人：
KAMAL D MEHTA
金额：
$ 37.5万
依托单位：
OHIO STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2004
资助国家：
美国
起止时间：
2004-12-06 至 2011-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7653553
关键词：
1,2-diacylglycerol Abbreviations Accounting Adipocytes Adipose tissue Affect Age Aging Anabolism Animals Antiatherogenic Apolipoprotein E Apolipoproteins B Arterial Fatty Streak Arts Atherosclerosis Binding Binding Proteins Blood Circulation Blood Vessels Brown Fat Buffers Cardiovascular Diseases Cause of Death Cell Nucleus Central obesity Cessation of life Cholesterol Cholesterol Homeostasis Complex Coronary Arteriosclerosis Cultured Cells Cytosol DNA-Protein Interaction Death Rate Developed Countries Development Diabetes Mellitus Diagnosis Diet Diet Habits Dietary Cholesterol Diglycerides Disease Dyslipidemias Endocrine Epidemic Etiology Evaluation Event Fatty acid glycerol esters Functional disorder Gene Expression Genes Genetic Genetic Transcription Goals Golgi Apparatus Heart Diseases Helix-Turn-Helix Motifs Hepatic Hepatocyte Histone H3 Homeostasis Human Hydroxymethylglutaryl-CoA Reductase Inhibitors Hyperglycemia Hypertriglyceridemia Inflammation Insulin Receptor Insulin Resistance Interleukin-6 Investigation Knock-out Knockout Mice Knowledge LDL Cholesterol Lipoproteins Link Lipids Liver Low Density Lipoprotein Receptor Low-Density Lipoproteins MAPK7 gene Mediating Membrane Metabolic Modification Molecular Molecular Biology Mus Mutant Strains Mice Nuclear Obesity Pathogenesis Patients Phenotype Phosphorylation Phosphotransferases Physiological Physiology Plasma Play Population Prevention Preventive Process Protein Binding Protein Isoforms Protein Kinase Protein Kinase C Proto-Oncogene Proteins c-akt Regulation Response Elements Risk Factors Role Serine Signal Pathway Signal Transduction Smoke Smoking Sterols Stress Stroke Techniques Time Tissues Transgenic Mice Transgenic Organisms Triglycerides Tumor Necrosis Factor-alpha Tumor Necrosis Factors United States Up-Regulation Vascular Cell Adhesion Molecule-1 Very low density lipoprotein Weather Work adipokines atherogenesis base citrate carrier diabetic disorder prevention fatty acid-binding proteins feeding gain of function human NOS3 protein hypercholesterolemia in vivo inhibitor/antagonist lifestyle factors link protein lipid disorder loss of function mouse model non-diabetic overexpression prevent promoter protein complex protein kinase C beta public health relevance receptor expression response ruboxistaurin transcription factor trend uptake

项目摘要

DESCRIPTION (provided by applicant): Every year in the United States nearly 1 million deaths occur among the 7 million people affected with cardiovascular diseases. The dominant underlying factor for this disease includes elevated plasma low density lipoprotein (LDL)-cholesterol levels in association with hypertriglyceridemia, abdominal obesity, or insulin resistance. The plasma levels of LDL are strongly influenced by dietary cholesterol and body's ability to store and metabolize ingested cholesterol. Considering that adipose tissue accumulates one of the largest pools of exchangeable free cholesterol, there is no information available regarding the role and regulation of adipose LDL receptors and its relationship to whole body cholesterol homeostasis. Also, our knowledge of the signaling pathway controlling adipose endocrine and lipo-metabolic functions through sterol-response element binding protein-1c (SREBP-1c) is limited, as is the role of this kinase in diet-induced atherosclerosis. We previously showed, for the first time, involvement of specific isoforms of protein kinase C (PKC) in regulating hepatic LDL receptor expression. In order to extend these studies to whole animal, we have been studying consequences of PKCbeta deficiency on lipid homeostasis. Based on our most recent observations linking PKCbeta deficiency to reduced plasma LDL levels, increased adipose nuclear SREBP-1c resulting in LDL receptor induction, and changes in plasma adipokines levels, we propose that PKCbeta plays a critical role in cholesterol homeostasis by regulating adipose SREBP-1c processing, thus regulating genes of lipid homeostasis and atherosclerosis. In Specific Aim 1, role of PKCbeta in LDL homeostasis will be established by evaluating effects of PKCbeta deficiency on hepatic biosynthesis and clearance, as well as adipose uptake of plasma LDL. To understand the molecular basis, we will also determine PKCbeta-dependent changes in the adipose gene expression and whether overexpression of adipose PKCbeta rescues the phenotype or adipose-specific PKCbeta deficiency alone can account for this phenotype. Specific Aim beta will define the nuclear and cytoplasmic events at the molecular level by which PKCbeta deficiency promotes nuclear accumulation of SREBP-1c and induction of adipose LDL receptors, without affecting hepatic LDL receptor expression. Finally, Specific Aim 3 will investigate the role of PKCbeta in cholesterol-rich-diet-induced atherosclerosis in PKCbeta-/- x ApoE-/- mice under diabetic or nondiabetic conditions. We already have these mice and initial results are very encouraging and have the potential to provide the molecular basis of diabetes-induced atherosclerosis and an alternative to statin. The proposed studies will not only establish the role of PKCbeta in regulating whole body cholesterol homeostasis, but will also identify genes regulated by this kinase, to correlate regulatory mechanisms to animal physiology. Accomplishment of the above aims will unravel a central signaling component that may control dyslipidemia and atherosclerosis by regulating adipose tissue physiology; modulation of its activity may be the preferable mode for the treatment of lipid disorders and prevention of atherosclerosis in the beta1st century. PUBLIC HEALTH RELEVANCE: Cardiovascular disease remains the leading cause of death in industrialized nations despite major advances in its diagnosis, treatment, and prevention. The underlying aetiology is not clarified, but includes a strong genetic component as well as lifestyle factors such as physical inactivity, dietary habits and smoking. While there has been a trend over the last half century showing a general decline in the age-adjusted death rates of heart disease and stroke, the increasing epidemics of obesity, followed closely by insulin resistance and diabetes, will likely slow the decline and reverse this trend. It is both necessary and timely to define roles of protein kinase Cbeta isoform that simultaneously modify all risk factors. The greatest potential for arresting this epidemic is likely to come through a clearer understanding of its molecular pathogenesis to develop rational and mechanism based therapy.

描述（由申请人提供）：在美国，每年有 700 万人患有心血管疾病，其中近 100 万人死亡。这种疾病的主要潜在因素包括与高甘油三酯血症、腹部肥胖或胰岛素抵抗相关的血浆低密度脂蛋白（LDL）胆固醇水平升高。低密度脂蛋白的血浆水平受到饮食胆固醇和身体储存和代谢摄入胆固醇的能力的强烈影响。考虑到脂肪组织是最大的可交换游离胆固醇库之一，目前还没有关于脂肪 LDL 受体的作用和调节及其与全身胆固醇稳态关系的信息。此外，我们对通过甾醇反应元件结合蛋白-1c (SREBP-1c) 控制脂肪内分泌和脂肪代谢功能的信号通路的了解有限，该激酶在饮食诱导的动脉粥样硬化中的作用也是有限的。我们之前首次证明蛋白激酶 C (PKC) 的特定亚型参与调节肝脏 LDL 受体表达。为了将这些研究扩展到整个动物，我们一直在研究 PKCbeta 缺乏对脂质稳态的影响。根据我们最近的观察，PKCbeta 缺乏与血浆 LDL 水平降低、脂肪核 SREBP-1c 增加导致 LDL 受体诱导以及血浆脂肪因子水平变化有关，我们认为 PKCbeta 通过调节脂肪 SREBP-在胆固醇稳态中发挥着关键作用。 1c 处理，从而调节脂质稳态和动脉粥样硬化的基因。在具体目标 1 中，将通过评估 PKCbeta 缺乏对肝脏生物合成和清除以及血浆 LDL 脂肪摄取的影响来确定 PKCbeta 在 LDL 稳态中的作用。为了了解分子基础，我们还将确定脂肪基因表达中 PKCbeta 依赖性的变化，以及脂肪 PKCbeta 的过度表达是否可以挽救该表型，或者脂肪特异性 PKCbeta 缺陷是否可以单独解释该表型。具体的 Aim beta 将在分子水平上定义核和细胞质事件，PKCbeta 缺陷通过这些事件促进 SREBP-1c 的核积累和脂肪 LDL 受体的诱导，而不影响肝脏 LDL 受体的表达。最后，特定目标 3 将研究 PKCbeta 在糖尿病或非糖尿病条件下 PKCbeta-/- x ApoE-/- 小鼠中富含胆固醇饮食诱导的动脉粥样硬化中的作用。我们已经有了这些小鼠，初步结果非常令人鼓舞，有可能为糖尿病引起的动脉粥样硬化提供分子基础，并成为他汀类药物的替代品。拟议的研究不仅将确定 PKCbeta 在调节全身胆固醇稳态中的作用，还将鉴定受该激酶调节的基因，将调节机制与动物生理学联系起来。上述目标的实现将揭示一个可以通过调节脂肪组织生理学来控制血脂异常和动脉粥样硬化的中央信号传导成分；调节其活性可能是本世纪治疗脂质紊乱和预防动脉粥样硬化的优选模式。公共卫生相关性：尽管心血管疾病的诊断、治疗和预防方面取得了重大进展，但它仍然是工业化国家死亡的主要原因。潜在的病因尚不清楚，但包括强大的遗传因素以及生活方式因素，如缺乏身体活动、饮食习惯和吸烟。尽管过去半个世纪的趋势显示，心脏病和中风的年龄调整死亡率普遍下降，但肥胖症的日益流行，以及紧随其后的胰岛素抵抗和糖尿病，可能会减缓下降速度并扭转这一趋势。趋势。明确蛋白激酶 Cbeta 同工型同时改变所有危险因素的作用是必要且及时的。遏制这种流行病的最大潜力可能来自对其分子发病机制的更清晰了解，以开发合理的、基于机制的治疗方法。