Assembly and Secretion of ApoB Containing Lipoproteins

含 ApoB 脂蛋白的组装和分泌

• 批准号: 7791358
• 负责人: HENRY N GINSBERG
• 金额: $ 40.25万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 1996
• 资助国家: 美国
• 起止时间: 1996-08-01 至 2012-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7791358
• 关键词: Affect; Albumins; Animal Model; Animals; Antisense Oligonucleotides; Apolipoproteins B; Area; Belief; Binding; Blood Circulation; Characteristics; Cholesterol Esters; Chromosomes, Human, Pair 10; Complex; Development; Diet; Dyslipidemias; Endoplasmic Reticulum; Fatty Acids; Fatty Liver; Fatty acid glycerol esters; Goals; Hepatic; Hepatocyte; Homologous Gene; Human; Hyperlipidemia; Hypertriglyceridemia; In Vitro; Individual; Insulin; Insulin Receptor; Insulin Resistance; Investigation; Knock-out; Laboratories; Lead; Link; Lipids; Lipoproteins; Liver; Mediating; Modeling; Molecular; Molecular Chaperones; Mus; Non-Insulin-Dependent Diabetes Mellitus; Pathway interactions; Phosphoric Monoester Hydrolases; Plasma; Play; Proteins; Relative (related person); Research Personnel; Role; Series; Source; Staging; Stimulus; Testing; Tissues; Translations; Triglycerides; Work; density; endoplasmic reticulum stress; fatty acid metabolism; in vitro Model; in vivo; in vivo Model; insight; insulin signaling; interest; lipid biosynthesis; mouse model; novel strategies; particle; research study; response; tensin; uptake

DESCRIPTION (provided by applicant): Increased secretion of apoliprotein B (apoB)-lipoproteins (Lps) characterizes both animal models and humans with dyslipidemia accompanying IR and type 2 diabetes mellitus (T2DM). The goal of the proposed studies is to provide new and unique insights into the integrated roles that hepatic fatty acids (FA) and triglycerides (TG), plasma FA, and hepatic insulin signaling play in determining both the secretion of apoB- Lps and development of hepatic steatosis. Of particular interest is the question: Why does hepatic steatosis occurs despite increased secretion of apoB-Lps in animals and people with IR. Our first hypothesis focuses on the roles of hepatic FA and TG on the assembly and secretion of apoB-Lps. The 3 aims under Hypothesis 1, test our belief that increased hepatic TG, from any source, is a potent determinant of the quantity of TG added to each apoB-Lp, but has only a minimal to modest effect on the number of particles secreted. We believe that the inability of increased hepatic TG to adequately stimulate secretion of increased numbers of apoB-Lps predisposes to steatosis. By contrast, we propose that increased uptake of circulating FA by the liver potently stimulates the secretion of increased numbers of apoB-Lps, potentially protecting against steatosis while possibly worsening the dyslipidemia. Importantly, we believe that FA- mediated stimulation of apoB-Lp secretion is independent of its incorporation into a common TG pool, and that FA from hepatic DNS do not effectively stimulate apoB-Lp secretion. The second hypothesis focuses on insulin-mediated degradation of apoB. The 4 aims under Hypothesis 2 focus on whether the effects of hepatic insulin signaling on apoB-Lp secretion will be modulated by hepatic TG and by FA from the circulation. We believe that increased hepatic TG will reduce insulin-mediated post-ER degradation of apoB while increased hepatic uptake of FA will reduce both insulin-mediated ER and post-ER degradation of apoB. Reduced hepatic insulin signaling will cause more apoB secretion and less hepatic TG, irrespective of prevailing hepatic synthesis of TG or FA flux. Finally, Hypothesis 3 and the aims that follow will focus on the possibility that ER stress, mediated by high fat diets or insulin resistance, alters apoB secretion. If ER stress partially inhibits apoB-Lp secretion that would predispose to steatosis. All of these studies will lead to a clearer understanding of, and new approaches to the treatment of dyslipidemia and hepatic steatosis.

描述（由申请人提供）：载脂蛋白B（APOB） - 脂蛋白（LPS）的分泌增加，表征了动物模型和人类患有IR和2型糖尿病伴随血脂异常的人（T2DM）。拟议的研究的目的是为肝脂肪酸（FA）和甘油三酸酯（TG），血浆FA和肝胰岛素信号传递在确定apob-lps的分泌以及肝Steatosis的发育中发挥作用的综合作用提供新的独特见解。特别值得关注的是：尽管动物和患有IR的人的APOB-LPS的分泌增加，但肝脂肪变性为什么会发生肝脂肪变性。我们的第一个假设侧重于肝FA和TG在APOB-LPS组装和分泌中的作用。在假设1下的3个目标，测试了我们的信念，即从任何来源提高肝Tg是对每个APOB-LP添加的TG量的有效决定因素，但对分泌的粒子数量的效果最小至少。我们认为，增加肝TG无法充分刺激apob-lps数量增加的脂肪症的分泌。相比之下，我们建议通过肝脏增加循环FA的吸收会有效地刺激APOB-LPS数量增加的分泌，从而可能预防脂肪变性，同时可能使血脂异常恶化。重要的是，我们认为对APOB-LP分泌的FA介导的刺激独立于将其掺入常见的TG库中，并且肝DNS中的FA不会有效地刺激APOB-LP分泌。第二个假设的重点是胰岛素介导的APOB降解。假设2下的4个目标集中在肝胰岛素信号传导对APOB-LP分泌的影响是否会通过肝TG和FA从循环中调节。我们认为，增加的肝TG会减少APOB的胰岛素介导的后降解后降解，同时增加FA的肝脏摄取将减少胰岛素介导的ER和APOB的后ER后降解。减少的肝胰岛素信号传导将导致更多的APOB分泌和较少的肝TG，而与TG或FA通量的肝合成无关。最后，假设3和随后的目标将集中于高脂饮食或胰岛素抵抗性介导的ER压力的可能性，改变了APOB的分泌。如果ER应力部分抑制APOB-LP分泌，而APOB-LP分泌会易于脂肪变性。所有这些研究将导致对血脂异常和肝脂肪变性治疗的新方法和新方法。