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：
7894724
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 2013-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7894724
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）：每年在美国患有心血管疾病的700万人中发生近100万人死亡。该疾病的主要潜在因子包括血浆低密度脂蛋白（LDL） - 胆固醇水平与高甘油三酸酯，腹部肥胖或胰岛素抵抗有关。 LDL的血浆水平受饮食中胆固醇和人体储存和代谢摄入胆固醇的能力的强烈影响。考虑到脂肪组织会积累最大的可交换胆固醇池之一，因此没有有关脂肪LDL受体的作用和调节的信息及其与全身胆固醇稳态的关系。同样，我们对通过固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受到限制，这种激酶在饮食诱导的动脉粥样硬化中的作用也是有限的。我们先前首次展示了蛋白激酶C（PKC）的特定同工型在调节肝LDL受体表达中。为了将这些研究扩展到整个动物，我们一直在研究PKCBETA缺乏症对脂质稳态的后果。 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动脉粥样硬化。在特定的目标1中，将通过评估PKCBETA缺乏对肝生物合成和清除的影响以及血浆LDL的脂肪吸收来确定PKCBETA在LDL稳态中的作用。为了理解分子基础，我们还将确定脂肪基因表达的PKCBETA依赖性变化，以及脂肪PKCBETA的过表达是否可以挽救表型或脂肪特异性的PKCBETA缺乏症，这可以解释此表型。特定的AIM Beta将在分子水平上定义核和细胞质事件，而PKCBETA缺乏促进SREBP-1C的核积累和诱导脂肪LDL受体，而不会影响肝LDL受体表达。最后，具体的目标3将研究PKCBETA在糖尿病或非糖尿病性疾病下PKCBETA - / - X APOE-/ - 小鼠中PKCBETA在富含胆固醇含量的动脉粥样硬化中的作用。我们已经有了这些小鼠，最初的结果非常令人鼓舞，并且有可能提供糖尿病诱导的动脉粥样硬化和汀类药物的替代方案的分子基础。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，而且还将确定该激酶调节的基因，以将调节机制与动物生理学相关。实现上述目的将揭示一个中心信号成分，该信号成分可能通过调节脂肪组织生理来控制血脂异常和动脉粥样硬化。对其活性的调节可能是治疗脂质疾病和预防beta1世纪动脉粥样硬化的优选模式。公共卫生相关性：尽管其诊断，治疗和预防取得了重大进展，但心血管疾病仍然是工业化国家死亡的主要原因。潜在的病因尚未澄清，但包括强大的遗传成分以及生活方式因素，例如身体不活跃，饮食习惯和吸烟。尽管过去半个世纪一直存在一种趋势，表明心脏病和中风的年龄调整后的死亡率普遍下降，但肥胖的流行病的日益增加，紧随其后的是胰岛素抵抗和糖尿病，可能会减慢下降并逆转这一趋势。定义蛋白激酶CBETA同工型的作用既是必要且及时的，从而同时改变了所有危险因素。阻止这种流行病的最大潜力可能是通过对其分子发病机理的更清晰的理解来发展基于理性和机制的治疗。

项目成果

期刊论文数量（8）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Exercise protects against diet-induced insulin resistance through downregulation of protein kinase Cβ in mice.

DOI：
10.1371/journal.pone.0081364
发表时间：
2013
期刊：
PloS one
影响因子：
3.7
作者：
Rao X;Zhong J;Xu X;Jordan B;Maurya S;Braunstein Z;Wang TY;Huang W;Aggarwal S;Periasamy M;Rajagopalan S;Mehta K;Sun Q
通讯作者：
Sun Q

Loss of protein kinase Cbeta function protects mice against diet-induced obesity and development of hepatic steatosis and insulin resistance.