DIETARY FAT REGULATION OF HEPATIC GENE EXPRESSION

膳食脂肪与包括胰岛素在内的几种疾病有关 抵抗、肥胖、高血压、动脉粥样硬化和某些类型的 癌的膳食脂肪的数量和类型都有助于 这些疾病的发生和发展。最近的实验 有证据表明，脂肪的作用是针对细胞的， 它涉及快速和适应性过程。我们的研究 集中在众所周知的抑制肝脏脂肪生成的饮食 多不饱和脂肪酸（PUFA）。 多不饱和脂肪酸对肝脏脂肪生成的影响 导致极低密度脂蛋白（VLDL）输出下降 和抑制血清甘油三酯（作为VLDL）水平。 我们的研究 已经表明PUFA通过抑制肝脏新生脂肪生成， 基因的转录编码的关键酶参与这两个 脂肪生成和糖酵解。 使用两种模型，即肝S14基因 （脂肪生成基因模型）和L-丙酮酸激酶（糖酵解基因模型）， 我们已经证明PUFA作用的分子靶点是顺式- 调节元件（PUFA-RE）位于近端启动子内， 这些基因。 PUFA-RE作为PUFA调节因子（PUFA- RF）干扰激素[三碘甲状腺原氨酸（T3）和胰岛素] 基因转录的激活，即显性阴性对照。的 提出了以下研究以进一步表征分子 PUFA作用的基础：1）使用原始的转染方法， 肝细胞来定义足够的DNA序列， PUFA介导的S14基因抑制所必需的; 2）使用 转染方法，以了解PUFA-RE如何在细胞内发挥作用。 近端启动子元件和上游启动子调控元件的背景 增强子;和3）分离和表征PUFA-RF以进一步定义 PUFA介导的干扰激素调节的机制 基因转录从这些研究中获得的信息将 具有重要的生物医学意义，因为阐明了 多不饱和脂肪酸调控脂肪生成基因的分子机制 转录。这些研究对小说的发展可能是有益的 降血脂剂和抗肥胖剂。最后，我们将获得新的见解 多不饱和脂肪酸对人体健康和发育的影响以及脂肪酸 对激素调节的影响可能有助于这种进展， 肥胖、胰岛素抵抗、心血管疾病和 致癌作用

Dietary fat has been linked to several diseases including insulin resistance, obesity, hypertension, atherosclerosis and certain types of cancers. Both the quantity and type of dietary fat contribute to the development and progression of these diseases. Recent experimental evidence indicates that the effect of fat is directed at the cellular level and involves both rapid and adaptive processes. Our studies have focused on the well-known suppression of hepatic lipogenesis by dietary polyunsaturated fatty acids (PUFA). PUFA effects on hepatic lipogenesis contribute to the decline in very low density lipoprotein (VLDL) output and a suppression of serum triglyceride (as VLDL) levels. Our studies have shown that PUFA suppress hepatic de novo lipogenesis by inhibiting the transcription of genes encoding key enzymes involved in both lipogenesis and glycolysis. Using two models, i.e. the hepatic S14 gene (lipogenic gene model) and L-pyruvate kinase (glycolytic gene model), we have shown that the molecular targets for PUFA action are cis- regulatory elements (PUFA-RE) located within the proximal promoters of these genes. PUFA-RE serve as targets for PUFA-regulated factors (PUFA- RF) that interfere with the hormonal [triiodothyronine (T3) and insulin] activation of gene transcription, i.e. dominant negative control. The following studies are proposed to characterize further the molecular basis of PUFA action: 1) to use a transfection approach of primal hepatocytes to define the DNA sequences that are sufficient and necessary for PUFA-mediated suppression of the S14 gene; 2) to use a transfection approach to understand how PUFA-RE function within the context of the proximal promoter elements and upstream hormone-regulated enhancers; and 3) to isolate and characterize PUFA-RF to define further the mechanism of PUFA-mediated interference of hormone regulation of gene transcription. The information gained from these studies will be of significant biomedical importance because of the elucidation of the molecular mechanisms of PUFA-mediated control of lipogenic gene transcription. These studies may be useful in the development of novel hypolipemic and anti-obesity agents. Finally, we will obtain new insight into PUFA effects on human health and development and how fatty acid effects on hormonal regulation may contribute to the progression of such diseases as obesity, insulin resistance, cardiovascular disease and carcinogenesis.