Lipid transport in the intestine

肠道中的脂质运输

• 批准号: 9212802
• 负责人: Judith Storch
• 金额: $ 39.19万
• 依托单位: RUTGERS, THE STATE UNIV OF N.J.
• 依托单位国家: 美国
• 财政年份: 1987
• 资助国家: 美国
• 起止时间: 1987-05-01 至 2020-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9212802
• 关键词: 2-arachidonylglycerol; Ablation; Address; Adipose tissue; Albumins; Appetite Stimulants; Assimilations; Binding; Binding Proteins; Biophysics; Body Weight; Body fat; Brain; CB1 knockout; CB1 receptor antagonist; CNR1 gene; Calories; Cells; Cytosol; Diet; Dietary Fats; Digestion; Disease; Eating; Endocannabinoids; Energy Metabolism; Enterocytes; Exercise; Exhibits; Fatty Acid-Binding Protein 1; Fatty Acids; Fatty acid glycerol esters; Financial compensation; Gastrointestinal tract structure; Gene Expression; Glucose Intolerance; Health; Hepatic; High Fat Diet; Homeostasis; Homologous Protein; Human; Hyperphagia; Individual; Intestines; Intracellular Transport; Kinetics; Knock-out; Knockout Mice; Lead; Lipids; Liver; Malabsorption Syndromes; Mediating; Metabolic; Metabolism; Monoglycerides; Mucous Membrane; Mus; Muscle; Obesity; Partner in relationship; Peptides; Performance; Phenotype; Play; Process; Proteins; Publishing; Rest; Role; Small Intestines; Source; Testing; Thinness; Time; Tissues; Transfection; Viral; Weight Gain; Work; adeno-associated viral vector; anandamide; base; defined contribution; endogenous cannabinoid system; fatty acid metabolism; fatty acid-binding proteins; glucose tolerance; improved; in vivo; intestinal fatty acid binding protein; lean body mass; lipid metabolism; lipid transport; metabolomics; novel; promoter; public health relevance; sensor; uptake; villin; western diet

 DESCRIPTION (provided by applicant): Dietary lipid is important both quantitatively and qualitatively to human health, and intestinal processing of exogenous lipid is central to its assimilation. While much is known about luminal digestion of dietary lipid, its intracellular transport and processing are less well understood. These studies will focus on the two different fatty acid-binding proteins (FABPs) which are expressed in the enterocyte, intestinal-FABP and liver-FABP (IFABP and LFABP). While thought to be critical for enterocyte lipid trafficking, this has not been directly demonstrated. Nor is it clear why two homologous proteins that both bind FAs, are co-expressed in the enterocyte. Our earlier kinetics studies demonstrated marked differences between the proteins, suggesting that IFABP and LFABP are likely to have distinct functions We have now compared mice null for these FABPs for the first time, and the remarkable phenotypic differences observed indicate that they indeed have at least some unique roles, not only in enterocyte lipid metabolism, but even more so by leading to markedly different effects on whole body energy homeostasis. Specifically, we find that high fat-fed LFABP-/- mice are hyperphagic and markedly obese, yet do not display glucose intolerance and have improved exercise performance, thus displaying a "metabolically healthy obese" (MHO) phenotype. The IFABP-/- mouse is also "healthier" than WT, with improved glucose tolerance and more efficient intestinal lipid secretion. However in marked contrast to the LFABP-/-, the high fat-fed IFABP-/- mouse weighs less and accumulates less body fat and more lean mass than WT mice. Both null mice studied are global knockouts, and while IFABP is normally expressed only in intestine, LFABP is also highly expressed in liver, thus we do not yet know whether the dramatic changes in LFABP-/- mice are due to LFABP in intestine, liver, or both. It is also not yet known how loss of enterocyte IFABP leads to a lean phenotype. Interestingly, we have found changes in intestinal metabolism of fatty acids and monoacylglycerols and in levels of mucosal endocannabinoids (EC), in particular the MG 2-arachidonoyl glycerol, and hypothesize that these tissue-level effects of FABP ablation contribute, at least in part, to the whole body phenotypes. Based on these observations and questions, our aims are to 1) determine whether the hyperphagia and obesity observed in the LFABP-/- mouse are mediated via the EC system; 2) explore the mechanisms by which ablation of IFABP leads to decreased fat mass and body weight and increased lean body mass; 3) use our newly generated LFABP/IFABP double knockout mouse (L/I-DKO) to definitively determine whether the enterocyte FABPs are required for bulk lipid uptake; and 4) define the contributions of liver LFABP vs. intestinal FABP to the MHO LFABP-/- phenotype, and the contributions of intestinal FABPs (L + IFABP) vs. hepatic FABP (LFABP) to the downstream systemic effects of intestinal lipid processing. The proposed studies will use the L/I-DKO mouse, mice generated by conditional deletions of liver LFABP or intestinal LFABP, and adeno-associated viral replacement of LFABP vs. IFABP in the LFABP-/- and L/I-DKO liver, to provide important new information about enterocyte lipid transport and processing, and their relationships to systemic fuel metabolism.

 描述（由适用提供）：饮食脂质在定量和质量上对人类健康都很重要，外源脂质的肠道加工对于同化的核心是核心。尽管对饮食脂质的腔消化知之甚少，但其细胞内的运输和加工知之甚少。这些研究将集中于两种不同的脂肪酸结合蛋白（FABP），这些蛋白质（FABPS）在肠细胞，肠道肠和肝脏-FABP（IFABP和LFABP）中表达。虽然认为对于肠球菌脂质贩运至关重要，但尚未直接证明这一点。为什么两种结合Fas的同源蛋白在肠球细胞中共表达。我们较早的动力学研究表明，蛋白质之间存在明显的差异，这表明IFABP和LFABP现在首次比较了这些Fabps的无效的小鼠，并且观察到了显着的表型差异，表明它们的确表明它们确实具有至少在肠球脂质的载体上，而是在肠球脂化的效果中至少具有一些独特的作用，而在体现上却构成了相同的效果。具体而言，我们发现高脂肪喂养的LFABP - / - 小鼠是肥大的，肥胖了，但不显示葡萄糖intlerance并提高了运动性能，因此显示出“代谢健康的肥胖”（MHO）表型。 IFABP - / - 小鼠也比WT“更健康”，具有提高的葡萄糖耐量和更有效的肠脂质分泌。然而，与LFABP - / - 形成鲜明对比的是，高脂肪喂养的IFABP - / - 小鼠的重量较小，比WT小鼠积聚更少的体内脂肪，更瘦的质量。两种无效的小鼠研究都是全球敲除，尽管IFABP通常仅在肠道中表达，但LFABP在肝脏中也高度表达，因此我们尚不知道LFABP - / - 小鼠的急剧变化是由于Intestine，Liver或两者兼而有之。尚不知道肠肠细胞IFABP的损失如何导致瘦肉表型。有趣的是，我们发现脂肪酸和单酰基甘油的肠道代谢以及粘膜内源性大麻素（EC）的水平，尤其是Mg 2-芳香酰甘油，并假设这些fabp平流的这些组织级效应至少在整个身体上有效，在整个体外，这些组织级别会导致。基于这些观察结果和问题，我们的目的是1）确定在LFABP - / - 小鼠中观察到的肥大和肥胖是否是通过EC系统介导的； 2）探索IFABP消融导致脂肪质量和体重下降并增加体重的机制； 3）使用我们新生成的LFABP/IFABP双基因敲除鼠标（L/I-DKO）来定义是否需要大量脂质摄取的肠肠细胞Fabps；和4）定义肝脏LFABP与肠Fabp对MHO LFABP - / - 表型的贡献，以及肠Fabps（L + IFABP）与肝FABP（LFABP）对肠脂质脂质加工的下游全身效应的贡献。拟议的研究将使用L/I-DKO小鼠，由肝LFABP或肠LFABP的条件缺失产生的小鼠，以及LFABP与IFABP的腺相关病毒置换与IFABP与IFABP与IFABP相比 - / - - / - - 和L/I-DKO肝脏中的IFABP，以提供有关Enterocil lipId lipid tostons的重要新信息，并提供了摄入的contercob intocy and crocessit and Crocessing and Crocessing和他们的处理。