A unique role for apoC-III in intestinal lipoprotein synthesis and secretion

apoC-III 在肠道脂蛋白合成和分泌中的独特作用

• 批准号: 8679815
• 负责人: Alison Bloom Kohan
• 金额: $ 15.59万
• 依托单位: UNIVERSITY OF CONNECTICUT STORRS
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-16 至 2019-09-15
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8679815
• 关键词: Acyl Coenzyme A; Adenoviruses; Apolipoproteins C; Cardiovascular Diseases; Cell Culture System; Cells; Code; Coupled; Data; Defect; Diabetes Mellitus; Enterocytes; Epidemiologic Studies; Fatty acid glycerol esters; Future; Genes; Genetic Polymorphism; Goals; Hepatocyte; High Density Lipoproteins; Human; Hyperlipidemia; Hypertriglyceridemia; Injection of therapeutic agent; Intestinal Absorption; Intestines; Investigation; Knowledge; Lead; Lipids; Lipoproteins; Liver; Location; Lymph; Mediating; Metabolic Diseases; Modeling; Monoglycerides; Mucous Membrane; Mus; Nonesterified Fatty Acids; Pathway interactions; Plasma; Play; Research; Risk; Role; System; Tail; Testing; Tissues; Transgenic Mice; Triglycerides; Variant; Veins; Very low density lipoprotein; absorption; apolipoprotein B-48; apolipoprotein C-III; drug development; enzyme activity; hypolipidemia; knock-down; lipoprotein lipase; mutant; novel; overexpression; programs; public health relevance; research study; small hairpin RNA; therapeutic target; trafficking; type I diabetic

DESCRIPTION (provided by applicant): Apolipoprotein C-III (apoC-III) is an exchangeable lipoprotein produced by both the liver and intestine. The plasma concentration of apoC-III is elevated in type 1 diabetics and is an independent predictor of cardiovascular disease. ApoC-III is found on triglyceride-rich lipoproteins and high-density lipoproteins, and acts to raise plasma triglyceride levels through the inhibition of lipoprotein lipase activity, and by interfering with lipoprotein clearance by the liver. While significant progress has been made in understanding the mechanisms that govern these effects, the role of apoC-III in intestinal lipoprotein synthesis and secretion remains undefined. We have recently observed that whole body overexpression of apoC-III in apoC-III transgenic (Tg) mice results in inhibited intestinal TAG secretion from the enterocyte into lymph coupled with the retention of free fatty acid (FFA) and monoacylglycerol (MAG) precursors and a decrease in TAG within the enterocyte. This inhibitory effect of apoC-III in the intestinal cell is in contrast to studies in hepatocytes, which have correlated apoC-III expression with increased VLDL secretion. Our overall hypothesis is that apoC-III plays a unique role in the intestine and liver in lipoprotein synthesis and secretion. We will test the 3 possible mechanisms by which increased apoC-III would lead to inhibited TAG synthesis (that apoC-III directly inhibits 1) MGAT and/or DGAT enzyme activity; 2) FFA trafficking to the ER; or 3) the activation of FFA to fatty acyl- CoA) and will delineate a mechanistic role for apoC-III in intestinal lipid absorption and secretion. We will also investigate the functional importance of apoC-III in the intestine versus the liver using adenovirus to knockdown and overexpress apoC-III in mouse liver. Finally, we will investigate the role of human apoC-III polymorphisms on intestinal TAG secretion in primary mouse enteroid cultures. The completion of these aims will provide key knowledge about the role of apoC-III in mediating intestinal lipoprotein secretion and the potential of intestinal apoC-III as a therapeutic target.

描述（由申请人提供）： 载脂蛋白 C-III (apoC-III) 是由肝脏和肠道产生的可交换脂蛋白。 1 型糖尿病患者的 apoC-III 血浆浓度升高，是心血管疾病的独立预测因子。 ApoC-III 存在于富含甘油三酯的脂蛋白和高密度脂蛋白上，并通过抑制脂蛋白脂肪酶活性和干扰肝脏的脂蛋白清除来提高血浆甘油三酯水平。虽然在了解控制这些作用的机制方面已经取得了重大进展，但 apoC-III 在肠道脂蛋白合成和分泌中的作用仍不清楚。我们最近观察到，apoC-III 转基因 (Tg) 小鼠全身过度表达 apoC-III，导致肠道 TAG 分泌受到抑制。 肠上皮细胞进入淋巴液，同时游离脂肪酸 (FFA) 和单酰甘油 (MAG) 前体的保留以及肠上皮细胞内 TAG 的减少。 apoC-III 在肠细胞中的这种抑制作用与肝细胞中的研究形成鲜明对比，肝细胞中的 apoC-III 表达与 VLDL 分泌增加相关。我们的总体假设是apoC-III 在肠和肝脏的脂蛋白合成和分泌中发挥独特的作用。我们将测试 3 种可能的机制，通过这些机制，apoC-III 增加会导致 TAG 合成受到抑制（apoC-III 直接抑制 1）MGAT 和/或 DGAT 酶活性； 2) FFA 贩运至急诊室；或 3) FFA 活化为脂酰辅酶 A)，并将描述 apoC-III 在肠道脂质吸收和分泌中的机制作用。我们还将使用腺病毒敲低和过度表达小鼠肝脏中的 apoC-III，研究 apoC-III 在肠道中与肝脏中的功能重要性。最后，我们将研究人 apoC-III 多态性对原代小鼠肠样培养物中肠道 TAG 分泌的作用。这些目标的完成将提供有关 apoC-III 在介导肠道脂蛋白分泌中的作用以及肠道 apoC-III 作为治疗靶点的潜力的关键知识。