DIETARY FAT REGULATION OF HEPATIC GENE EXPRESSION

膳食脂肪对肝基因表达的调节

• 批准号: 7385076
• 负责人: DONALD B JUMP
• 金额: $ 29.89万
• 依托单位: OREGON STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1991
• 资助国家: 美国
• 起止时间: 1991-08-01 至 2010-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7385076
• 关键词: ADD-1 protein; Acids; Adenoviruses; Affect; Apolipoproteins; Arachidonic Acids; Atherosclerosis; Attention; Binding Proteins; Blood; Carbohydrates; Cells; Cellular Structures; Cholesterol; Chronic Disease; Clinical Data; Coronary Arteriosclerosis; Development; Diabetes Mellitus; Diet; Dietary Fats; Dietary Fatty Acid; Disease; Disease Progression; Docosahexaenoic Acids; Dyslipidemias; Eicosanoid Production; Eicosanoids; Eicosapentaenoic Acid; Enzyme Induction; Enzymes; Essential Fatty Acids; Extrahepatic; Fatty Acid Desaturases; Fatty Acids; Figs - dietary; Gene Expression; Gene Expression Regulation; Gene Targeting; Genetic Transcription; Hepatic; Hepatocyte; Hypertension; Inflammation; Inflammatory; LXRalpha protein; Leptin; Link; Lipids; Liver; Major Depressive Disorder; Malignant Neoplasms; Membrane; Membrane Lipids; Metabolic; Metabolic Diseases; Molecular; Mus; Nuclear; Obese Mice; Obesity; Oleic Acid; Oleic Acids; PPAR alpha; Pathway interactions; Peroxisome Proliferator-Activated Receptors; Physiology; Play; Polyunsaturated Fatty Acids; Rattus; Recombinants; Regulation; Regulatory Element; Risk Factors; Role; SRE-1 binding protein; Scheme; Signal Transduction; Sterols; Stroke; Structure; Tissues; Transcript; Triglycerides; base; blood lipid; desaturase; fatty acid elongases; fatty acid metabolism; insight; interest; mead acid; postnatal; receptor; transcription factor

DESCRIPTION (provided by applicant): The molecular basis of dietary fatty acid regulation of gene expression has gained considerable attention in recent years because of its contribution to chronic disease [obesity, diabetes & atherosclerosis]: Our studies have focused on dietary polyunsaturated fatty acid (PUFA: eicosapentaenoic acid [20:5n3] and docosahexaneoic acid [22:6n3]) control of three hepatic transcription factors, sterol regulatory element binding protein (SREBP-1c), peroxisome proliferator activated receptor (PPARalpha) and liver X receptor (LXRalpha). These studies have revealed new information on: a) dynamic & cell-specific PUFA regulation of each transcription factor; b) developmental regulation of SREBP-1c and its regulatory network, and c) a role for PPARalpha and SREBP-1 in PUFA synthesis; d) the regulation of fatty acid elongases & desaturases; e) induction of these enzymes generates fatty acids that do not normally accumulate in cells; these rare fatty acids impact cell signaling by affecting eicosanoid production. These findings have broad implications for metabolic regulation, particularly with regard to chronic diseases like diabetes, obesity and atherosclerosis, where clinical data links fatty acid metabolites to disease progression. There remains a poor understanding of the role fatty acid elongases play in hepatic and whole body physiology. We hypothesize that hepatic fatty acid elongation: a) regulates hepatic & extrahepatic (aortic and blood) fatty acid composition; b)/egulates key transcription factors [PPARalpha & SREBP-1 c]; and c) influences the onset or progression of chronic disease, e.g., diabetes, obesity or atherosclerosis. The specific aims are to: 1. Define the metabolic regulation of hepatic fatty acid elongases; 2. Define the role of PPARalpha and SREBP-1 in the regulation of fatty acid elongases; 3. Define the effects of fatty acid elongases on hepatocyte lipid composition and gene expression; 4. Determine how over expression of specific fatty acid elongases affects hepatic function, blood lipid composition and the onset of chronic disease.

描述（申请人提供）：近年来，膳食脂肪酸调控基因表达的分子基础因其对慢性疾病[肥胖、糖尿病和动脉粥样硬化]的贡献而受到了相当大的关注。我们的研究主要集中在膳食多不饱和脂肪酸（PUFA）：二十碳五烯酸[20:5 . n3]和二十二碳六烯酸[22:6 . n3])对三种肝脏转录因子、甾醇调节元件结合蛋白（SREBP-1c）、过氧化物酶体增殖物激活受体（ppar - α）和肝脏X受体（lxr - α）的调控作用。这些研究揭示了以下方面的新信息：a)每个转录因子的动态和细胞特异性PUFA调控；b) SREBP-1c的发育调控及其调控网络，c) ppar和SREBP-1在PUFA合成中的作用；D)脂肪酸延长酶和去饱和酶的调控；E)这些酶的诱导产生通常不会在细胞中积累的脂肪酸；这些稀有脂肪酸通过影响类二十烷酸的产生来影响细胞信号传导。这些发现对代谢调节具有广泛的意义，特别是在糖尿病、肥胖和动脉粥样硬化等慢性疾病方面，临床数据将脂肪酸代谢物与疾病进展联系起来。目前对脂肪酸延长酶在肝脏和全身生理中的作用仍知之甚少。我们假设肝脂肪酸延伸：a)调节肝脏和肝外（主动脉和血液）脂肪酸组成；b)/调控关键转录因子[ppar - α和SREBP-1 c]；c)影响慢性疾病的发生或进展，如糖尿病、肥胖或动脉粥样硬化。具体目标是：1。明确肝脂肪酸延长酶的代谢调控；2. 明确ppar和SREBP-1在脂肪酸延长酶调控中的作用；3. 确定脂肪酸延长酶对肝细胞脂质组成和基因表达的影响；4. 确定特定脂肪酸延长酶的过度表达如何影响肝功能、血脂组成和慢性疾病的发病。