Apo B Translocation and Degradation

描述（由申请人提供）：含载脂蛋白b的肝脏产生在脂质代谢中起着不可或缺的作用。含载脂蛋白b产生的不平衡或其被肝脏清除与几种疾病有关，包括动脉粥样硬化、肥胖和糖尿病。利用培养的肝细胞和转基因小鼠获得的数据使我们假设含有脂蛋白的载脂蛋白B的肝脏分泌在转录后受到调节。在其翻译过程中，载脂蛋白B有两种代谢命运：在添加脂质形成脂蛋白颗粒的过程中转运到内质网（ER）的管腔，或通过泛素依赖的蛋白酶体途径降解。微粒体甘油三酯转移蛋白（MTP）和甘油脂（磷脂和甘油三酯）的供应在介导载脂蛋白B易位和组装成脂蛋白颗粒中起重要作用。根据在上一资助期内获得的新见解，我们将致力达致以下具体目标：

DESCRIPTION (provided by applicant): Hepatic production of apo B-containing lipoproteins plays an integral role in lipid metabolism. Imbalances of the production of apo B-containing lipoproteins or their removal by the liver are associated with several diseases including atherosclerosis, obesity and diabetes. Data obtained using cultured hepatocytes and genetically altered mice have led us to hypothesize that hepatic secretion of apo B containing lipoproteins is regulated post-transcriptionally. During its translation, apo B has two metabolic fates: translocation into the lumen of the endoplasmic reticulum (ER) during the addition of lipid to form a lipoprotein particle or degradation by an ubiquitin-dependent proteasome pathway. Microsomal triglyceride transfer protein (MTP) and the supply of glycerolipids (phospholipids and triglycerides) play an essential role in mediating apo B translocation and assembly into a lipoprotein particle. Based on new and intriguing insights gained during the previous funding period, we will direct our efforts to the following Specific Aims: Specific Aim 1: To define how COUP-TFII interacts with a conserved DR1 site in the MTP promoter and alters gene transcription in rat hepatoma cells and in vivo in the livers of mice. Specific Aim 2: To examine the role of ubiquitin-dependent proteasome degradation in regulating the metabolic fate of apo B in vivo in the livers of mice. Specific Aim 3: To examine the mechanism through which genetic deletion of Txnip alters the flow of carbon units into lipids and secretion of apo B-containing lipoproteins. Clearly, MTP-mediated translocation and lipid transfer is an effective target for ameliorating one of the most severe forms of hypercholesterolemia (for which most other drugs [e.g. statins] are ineffective; i.e., homozygous familial hypercholesterolemia). We are confident that our proposed studies will provide new insights that will add further proof to the feasibility and advance the therapeutic potential of controlling the apo B processing pathway.