DIETARY FAT REGULATION OF HEPATIC GENE EXPRESSION

摄入的膳食脂肪的数量和类型有助于 健康以及几种慢性疾病的发病和发展。的 肝脏在全身脂质合成和代谢中起中心作用。过去 PI进行的研究集中在确定 脂肪酸调控基因的转录编码蛋白质参与 脂肪酸的合成和氧化。这些研究揭示了3种不同的 脂肪酸控制肝脏脂质代谢的机制：a）高度 不饱和n-3脂肪酸激活过氧化物酶体增殖物 受体（PPAR α），并诱导参与基因的表达 过氧化物酶体和微粒体脂肪酸氧化; B）n-3和n-6多不饱和 脂肪酸（PUFA）抑制固醇反应元件的核含量 结合蛋白SREBP 1c。SREBP 1c在控制 脂质合成和储存; c）n-6 PUFA转化为活化的前列腺素类 实质细胞和培养的脂肪细胞中的G蛋白连接受体， 抑制编码特定脂肪生成基因的mRNA。在这三种途径中，PUFA 核SREBP 1c（nSREBP 1c）水平的控制似乎是调节的核心 肝脏脂质合成然而，这种控制的分子基础是 没有很好地理解。此外，研究表明SREBP 1c和 肥胖小鼠肝脏微粒体脂肪酸氧化。膳食脂肪控制 假设nSREBP 1c水平需要微粒体脂肪酸氧化， 会得到考验伴随肥胖的激素和/或营养素摄入的变化 改变微粒体PUFA代谢，影响SREBP 1c水平， 与肝脏脂质代谢失调有关。在这份报告中，四个目标 旨在回答以下问题：1）SREBP 1c如何 在功能上与核受体相互作用2)PUFA如何调节 肝脏SREBP 1c水平？3)微粒体脂肪酸代谢是否参与 调节nSREBP 1c丰度？4)脂肪酸代谢异常是否与 与nSREBP 1c和脂肪生成基因表达的失调， 肥胖老鼠肥胖是全球范围内日益严重的人类健康问题， 对于慢性疾病，如高血压，胰岛素抵抗性心脏病， 癌PPAR α和SREBP 1c是参与的关键肝脏转录因子 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.