METABOLIC REGULATION OF LIPID BIOGENESIS

本研究的长期目标有两个：1）确定 脂肪酸在调节硬脂酰辅酶A去饱和酶基因中的作用 在小鼠肝脏和脂肪组织中。 2)去了解分子 控制小鼠硬脂酰辅酶A去饱和酶表达的机制 分化前脂肪细胞和完全发育的脂肪细胞中的基因。 作为 为了解决第一个问题，我计划继续我的研究， 调节硬脂酰辅酶A去饱和酶表达的机制 无脂肪喂养的小鼠肝脏和脂肪组织中的基因 饮食和含有饱和或不饱和脂肪酸的饮食。 到 为了解决第二个问题，我计划将我的初步研究扩展到 在小鼠3 T3-L1分化过程中发生的调节机制 前脂肪细胞转化为脂肪细胞。 3 T3-L1的分化 前脂肪细胞转化为脂肪细胞， 在分子水平上研究细胞分化的系统。 硬脂酰辅酶A去饱和酶是生物合成不饱和脂肪酸的关键酶 脂肪酸以及调节这一过程。 我克隆了 确定了两个硬脂酰辅酶A去饱和酶基因的遗传结构 (SCD1和SCD 2），两者都在 前脂肪细胞分化，但不同的调节脂肪酸 在小鼠肝脏、脂肪和其他组织中。 这项建议的主要目的是确定脂肪酸 控制基因表达。 传统的分子生物学方法将是 用来帮助回答假设。 的具体目标 建议的研究将是：1）确定和排序的监管 控制两种硬脂酰辅酶A去饱和酶转录的元件 基因在前脂肪细胞分化过程中的作用。 2)来识别 与基因的控制元件相互作用的调节蛋白， 并确定其功能。 3)确定 脂肪酸作用于调节分化诱导的位点 小鼠肝脏和脂肪硬脂酰辅酶A去饱和酶mRNA，即是否通过 影响基因转录或通过改变特定mRNA 周转 下一个目标将是研究 这种监管。 这些研究可能阐明细胞分化的分子机制 以及对脂肪酸在调节 哺乳动物基因活性的研究可能有助于治疗心脏病 疾病

The LONG-TERM OBJECTIVES of this research are two fold: 1) to define the role of fatty acids in the regulation of the stearoyl-CoA desaturase genes in mouse liver and adipose tissue. 2) to understand the molecular mechanisms that control the expression of the mouse stearoyl-CoA desaturase genes in differentiating preadipocytes and fully developed adipocytes. As an approach to the first problem, I plan to continue my studies to the mechanisms that regulate the expression of the stearoyl-CoA desaturase genes in the liver and adipose tissue of mice that have been fed fat-free diets and diets containing either saturated or unsaturated fatty acids. To address the second problem, I plan to extend my initial studies on the regulatory mechanisms that occur during the differentiation of mouse 3T3-L1 preadipocytes into adipocytes in culture. The differentiation of 3T3-L1 preadipocytes into adipocytes in one of the few well characterized model systems available to study cellular differentiation at the molecular level. Stearoyl-CoA desaturase is a key enzyme in the biosynthesis of unsaturated fatty acids as well as the regulation of this process. I have cloned and determined the genetic organization of the two stearoyl-CoA desaturase gene (SCD1 and SCD2) both of which are transcriptionally activated during preadipocyte differentiation but are regulated differently by fatty acids in mouse liver, adipose and other tissues. The major aim of this proposal is to establish precisely how fatty acids control gene expression. Conventional molecular biology approaches will be used to help in answering the hypotheses. The SPECIFIC AIMS of the proposed research will be: 1) to identify and sequence the regulatory elements which control transcription of the two stearoyl-CoA desaturase gene during preadipocyte differentiation. 2) to identify the unique regulatory proteins which interact with the control elements of the genes, characterize them and determine their function. 3) to determine the site(s) at which fatty acids act to regulate the differential induction of the mouse liver and adipose stearoyl-CoA desaturase mRNAs, i.e. whether by affecting gene transcription or by changing the rate of specific mRNA turnover. The next objective will be to study the molecular mechanisms of this type of regulation. These studies may clarify molecular mechanisms of cellular differentiation and the new insight gained into the role of fatty acids in the regulation of gene activity in mammals may be useful in the treatment of heart disease.