DIETARY FAT REGULATION OF HEPATIC GENE EXPRESSION

描述（申请人提供）：近年来，膳食脂肪酸调节基因表达的分子基础受到了相当大的关注，因为它对慢性疾病[肥胖、糖尿病和动脉粥样硬化]的贡献：我们的研究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]）控制三种肝转录因子、固醇调节元件结合蛋白（SREBP-1c）、过氧化物酶体增殖物激活受体（PPARalpha）和肝X受体（LXR alpha）。这些研究揭示了以下方面的新信息：a）每种转录因子的动态和细胞特异性PUFA调节; B）SREBP-1c及其调节网络的发育调节; c）PPARalpha和SREBP-1在PUFA合成中的作用; d）脂肪酸延伸酶和去饱和酶的调节; e）这些酶的诱导产生通常不在细胞中积累的脂肪酸;这些稀有脂肪酸通过影响类花生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，特别是对于糖尿病、肥胖和动脉粥样硬化等慢性疾病，其中临床数据将脂肪酸代谢物与疾病进展联系起来。脂肪酸延长酶在肝脏和全身生理学中的作用仍缺乏了解。我们假设肝脂肪酸延长：a）调节肝和肝外（主动脉和血液）脂肪酸组成; B）调节关键转录因子[PPARalpha和SREBP-1 c];和c）影响慢性疾病的发作或进展，例如，糖尿病、肥胖症或动脉粥样硬化。具体目标是：1.明确肝脂肪酸延长酶的代谢调控; 2.明确PPARalpha和SREBP-1在调节脂肪酸延长酶中的作用; 3.明确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生。

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.