DIETARY FAT REGULATION OF HEPATIC GENE EXPRESSION

饮食中的脂肪与包括胰岛素在内的多种疾病有关 抵抗力、肥胖、高血压、动脉粥样硬化和某些类型的 癌症。膳食脂肪的数量和类型都对 这些疾病的发展和进展。最近的实验 有证据表明，脂肪的影响是针对细胞的。 在这一层面上，它既涉及快速进程，又涉及适应性进程。我们的研究已经 关注众所周知的饮食抑制肝脏脂肪生成 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)产量下降 以及抑制血清甘油三酯(如极低密度脂蛋白)水平。我们的研究 已表明多不饱和脂肪酸通过抑制肝脏新生脂肪生成来抑制肝脏新生脂肪生成 编码这两种关键酶的基因的转录 脂肪生成和糖酵解。使用两个模型，即肝脏S14基因 (生脂基因模型)和L-丙酮酸激酶(糖酵解基因模型)， 我们已经证明了多不饱和脂肪酸作用的分子靶标是顺式- 调控元件(PUFA-RE)位于PUFA近端启动子内 这些基因。PUFA-RE作为PUFA调节因子(PUFA-RE)的靶标 Rf)干扰激素[三碘甲腺原氨酸(T3)和胰岛素] 基因转录激活，即显性阴性对照。这个 建议进行以下研究以进一步确定分子的特征 多不饱和脂肪酸作用的基础：1)使用原始细胞的转染法 以确定足够的DNA序列 多不饱和脂肪酸介导的抑制S14基因所必需的；2)使用一种 用转染法了解PUFA-RE在细胞内的作用 近端启动子元件和上游激素调节的背景 3)分离和鉴定PUFA-RF，以进一步确定 多不饱和脂肪酸介导的激素调节作用机制 基因转录。从这些研究中获得的信息将是 具有重要的生物医学意义，因为阐明了 多不饱和脂肪酸对生脂基因调控的分子机制 抄写。这些研究可能会对小说的发展有所帮助 降血脂和抗肥胖剂。最后，我们将获得新的见解 多不饱和脂肪酸对人类健康和发育的影响以及脂肪酸如何 对激素调节的影响可能有助于此类疾病的进展 肥胖、胰岛素抵抗、心血管疾病和 致癌。

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.