Mechanisms and Tissue-Specific Contributions of Liver-Fatty Acid Binding Protein (LFABP) in Whole-Body Energy Homeostasis

肝脏脂肪酸结合蛋白（LFABP）在全身能量稳态中的机制和组织特异性贡献

• 批准号: 9401754
• 负责人: Atreju Lackey
• 金额: $ 3.76万
• 依托单位: RUTGERS, THE STATE UNIV OF N.J.
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-01 至 2019-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9401754
• 关键词: 2-arachidonylglycerol; Ablation; Address; Agonist; Albumins; Body Composition; Body Weight; CRISPR/Cas technology; Chronic; Diet; Dietary Fats; Eating; Endocannabinoids; Exercise; Exons; FABP1 gene; Family; Fatty Acid-Binding Protein 1; Fatty acid glycerol esters; Gastrointestinal tract structure; Gene Components; Gene Expression; Gene Proteins; Genes; Genetically Engineered Mouse; Glucose; Health; Hepatic; High Fat Diet; Histologic; Homeostasis; Human; Indirect Calorimetry; Ingestion; Insulin; Intestines; Intracellular Transport; Knock-out; Knockout Mice; Ligands; Lipids; Liver; LoxP-flanked allele; Metabolic; Metabolism; Methods; Modeling; Molecular Chaperones; Mouse Protein; Movement; Mus; Obesity; Obesity associated disease; PPAR alpha; Partner in relationship; Performance; Phenotype; Plasma; Play; Prevalence; Process; Proteins; Rest; Role; Signal Transduction; Site; Small Intestines; System; Tissues; Transcriptional Activation; Weight Gain; Wild Type Mouse; anandamide; base; endogenous cannabinoid system; endurance exercise; energy balance; fatty acid-binding proteins; glucose tolerance; improved; lipid metabolism; lipid transport; member; oxidation; promoter; sensor; transcription factor; uptake; villin

Project Summary/Abstract The quality and quantity of dietary lipid is important to many facets of human health. The ingestion of exogenous lipid has downstream effects on metabolically active tissues, such as the liver and the gastrointestinal (GI) tract. Many aspects of lipid transport and metabolism in the liver and GI tract are known, however the intracellular trafficking of lipids in these tissues, and the ramifications of that transport, are not fully understood. These studies will focus on the liver-fatty acid binding protein (LFABP), which is highly expressed in both the small intestine (SI) and the liver. Traditionally, LFABP has been considered to be a protein that is integral for lipid processing, assisting in the uptake and intracellular transport of lipid. Our recent studies have demonstrated that ablation of LFABP (LFABP-/-) in high fat (HF) fed mice results in dramatic effects on body weight and body composition when compared to wild-type (WT) mice. Interestingly, although HF fed LFABP-/- mice are markedly obese and hyperphagic, they display a metabolically healthy obese phenotype (MHO), with improved exercise performance and normal glucose tolerance. Studies performed in LFABP-null mice so far have only used global knock out mice, thus it is unknown if the dramatic changes in these mice are due to ablation of LFABP in the intestine, liver, or both tissues. Our recent studies have also demonstrated that HF fed LFABP-/- mice have elevated mucosal levels of the endocannabinoids (ECs), 2-arachidinoylglycerol and anandamide, which may contribute, in part, to the observed whole-body phenotype. Additionally, other groups have demonstrated that LFABP is able to interact with peroxisome-proliferator activated receptor alpha (PPARα), indicating that LFABP may play a role in whole-body energy balance by altering the activation of this transcription factor. Based on these observations, our aims are to 1) determine the tissue-specific contributions of intestinal-LFABP and liver-LFABP to the MHO phenotype that has been observed in whole-body LFABP-/- mice; and 2) determine if LFABP acts as a lipid sensor and chaperone, facilitating the movement of lipid ligands to alter signal transduction and the activity of transcription factors. The proposed studies will use conditional knock out (cKO) LFABP mice generated via the CRISPR/Cas9 system, providing new information on the role that LFABP plays in regulating whole body energy homeostasis.

项目总结/摘要 膳食脂质的质量和数量对人类健康的许多方面都很重要。摄入 外源性脂质对代谢活性组织如肝脏和肝细胞具有下游效应。 胃肠道（GI）。肝脏和胃肠道中脂质转运和代谢的许多方面是已知的， 然而，这些组织中脂质的细胞内运输以及该运输的分支并不完全 明白这些研究将集中在肝脏脂肪酸结合蛋白（LFABP），这是高表达 在小肠（SI）和肝脏中。传统上，LFABP被认为是一种蛋白质， 是脂质加工的组成部分，有助于脂质的摄取和细胞内转运。我们最近的研究 在高脂肪（HF）喂养的小鼠中，LFABP（LFABP-/-）的消融导致对身体的显著影响， 体重和身体组成。有趣的是，虽然HF喂食LFABP-/- 小鼠明显肥胖和贪食，它们显示代谢健康肥胖表型（MHO）， 改善运动表现和正常的葡萄糖耐量。迄今为止在LFABP缺失小鼠中进行的研究 我只使用了整体基因敲除小鼠，因此不知道这些小鼠的显著变化是否是由于 在肠、肝或这两种组织中消融LFABP。我们最近的研究也表明，HF 喂食LFABP-/-小鼠的内源性大麻素（EC）、2-花生酰甘油和 大麻素，这可能有助于，部分，观察到的全身表型。此外，其他团体 已经证明LFABP能够与过氧化物酶体增殖物激活受体α相互作用， (PPARα），表明LFABP可能通过改变这种激活在全身能量平衡中发挥作用。 转录因子基于这些观察，我们的目标是：1）确定组织特异性贡献 与在全身LFABP-/-中观察到的MHO表型相关， 2）确定LFABP是否作为脂质传感器和伴侣蛋白，促进脂质的运动， 配体来改变信号转导和转录因子的活性。拟议的研究将使用 通过CRISPR/Cas9系统产生的条件性敲除（cKO）LFABP小鼠，提供了新的信息 LFABP在调节全身能量平衡中的作用。