DIETARY FAT REGULATION OF HEPATIC GENE EXPRESSION

摄入的膳食脂肪的数量和类型对 健康以及几种慢性病的发生和发展。这个 肝脏在全身脂肪合成和代谢中起着核心作用。过去时 由PI进行的研究主要集中在定义 脂肪酸对编码蛋白基因转录的调节作用 脂肪酸的合成和氧化。这些研究揭示了三个不同的 肝脏脂肪代谢的脂肪酸调控机制：a)高度 不饱和n-3脂肪酸激活过氧化体增殖物 受体(PPARα)并诱导相关基因的表达 过氧化物型和微粒型脂肪酸氧化；b)n-3和n-6多不饱和 脂肪酸(PUFA)抑制类固醇反应元件的核含量 结合蛋白，SREBP1c。SREBP1c在控制沙门氏菌病中发挥重要作用 脂类合成和储存；c)n-6多不饱和脂肪酸转化为前列腺素的活性 实质细胞和培养的脂肪细胞中的G蛋白连接受体 抑制编码特定生脂基因的mRNAs。在这三条途径中，多不饱和脂肪酸 核SREBP1c(NSREBP1c)水平的控制似乎是调控的核心 肝脏脂肪合成的影响。然而，这种控制的分子基础是 不是很清楚。此外，研究表明SREBP1c和SREBP1c的调节失调 肥胖小鼠肝脏微粒体脂肪酸氧化。饮食中脂肪的控制 NSREBP1c水平需要微粒体脂肪酸氧化是一种假设 将会受到考验。肥胖时激素和/或营养素摄入量的变化 影响SREBP1c水平和贡献的微粒体多不饱和脂肪酸代谢改变 与肝脂代谢紊乱有关。在这项提案中，有四个目标 旨在回答以下问题：1)SREBP1c如何 功能上与核受体相互作用？2)多不饱和脂肪酸是如何调节的 肝脏SREBP1c水平？3)微粒体脂肪酸代谢是否参与 调节nSREBP1c丰度与脂肪酸代谢异常有关 肝组织中nSREBP1c和致脂基因表达的异常 肥胖的老鼠？肥胖是世界范围内日益严重的人类健康问题和危险因素 适用于慢性疾病，如高血压、胰岛素抵抗心脏病和 癌症。PPARα和SREBP1c是关键的肝脏转录因子 在合成/储存和氧化之间分配脂质。理解 这些因素如何参与正常和肥胖动物的这一过程 对人类健康有重要影响。

The quantity and type of dietary fat ingested contributes to health as well as the onset and progression of several chronic diseases. The liver plays a central role in whole body lipid synthesis and metabolism. Past studies conducted by the PI have focused on defining the molecular basis of fatty acid regulation of transcription of genes encoding proteins involved in fatty acid synthesis and oxidation. These studies have revealed 3 distinct mechanisms for fatty acid control of hepatic lipid metablosim: a) highly unsaturated n-3 fatty acids activate the peroxisome proliferator activated receptor (PPAR alpha) and induce the expression of genes involved in peroxisomal and microsomal fatty acid oxidation; b) n-3 and n-6 polyunsaturated fatty acids (PUFA) suppress the nuclear content of the sterol response element binding protein, SREBP1c. SREBP1c plays an important role in the control of lipid synthesis and storage; c) conversion of n-6 PUFA to prostanoids activated G-protein linked receptors in parenchymal cells and cultured adipocytes to suppress mRNAs encoding specific lipogenic genes. Of these 3 pathways, PUFA control of nuclear SREBP1c (nSREBP1c) level appears central to the regulation of hepatic lipid synthesis. However, the molecular basis for this control is not well understood. Moreover, studies show dysregulation of SREBP1c and microsomal fatty acid oxidation in livers of obese mice. Dietary fat control of nSREBP1c levels requires microsomal fatty acid oxidation is the hypothesis that will be tested. Changes in hormonal and/or nutrient intake accompanying obesity alter microsomal PUFA metabolism which impacts SREBP1c levels and contributes to the dysregulation of hepatic lipid metabolism. In this proposal,four aims are designed to answer the following questions: 1) How does SREBP1c functionally interact with nuclear receptors? 2) How does PUFA regulated hepatic SREBP1c levels? 3) Is microsomal fatty acid metabolism involved in regulating nSREBP1c abundance? 4) Is aberrant fatty acid metabolism associated with the dysregulation of nSREBP1c and lipogenic gene expression in livers of obese mice? Obesity is a growing human health issue worldwide and risk factor for chronic diseases, like hypertension, insulin resistance heart disease and cancer. PPAR alpha and SREBP1c are key hepatic transcription factors involved in partitioning lipid between synthesis/storage and oxidation. Understanding how these factors participate in this process in normal and obese animals will have important implications for human health.