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: 9555803
• 负责人: Atreju Lackey
• 金额: $ 3.81万
• 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/9555803
• 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; Mucous Membrane; 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.

项目摘要/摘要 饮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 外源脂质对代谢活性组织（例如肝脏和肝脏）具有下游影响 胃肠道（GI）。肝脏和胃肠道中脂质转运和代谢的许多方面都是已知的， 但是，这些组织中脂质的细胞内运输以及该转运的后果并不完全 理解齿。这些研究将集中于肝脂肪酸结合蛋白（LFABP），该蛋白高度表达 在小肠（SI）和肝脏中。传统上，LFABP被认为是一种蛋白质 脂质加工的积分，有助于脂质的摄取和细胞内转运。我们最近的研究已经 证明LFABP（LFABP - / - ）在高脂肪（HF）喂养小鼠中的消融会对人体产生巨大影响 与野生型（WT）小鼠相比，体重和身体成分。有趣的是，尽管HF喂LFABP - / - 小鼠显着肥胖和倍感，它们显示出代谢健康的肥胖表型（MHO），并带有 改善运动性能和正常的葡萄糖耐量。到目前为止，在LFABP-NULL小鼠中进行的研究 仅使用了全球敲除小鼠，因此，如果这些小鼠的戏剧性变化是由于 LFABP在肠，肝或两种组织中的消融。我们最近的研究也表明HF 喂养的LFABP - / - 小鼠的内源性大麻素（ECS），2-芳基丁酰甘油和 Anandamide，可能部分促进了观察到的全身表型。另外，其他小组 已经证明LFABP能够与过氧化物组增强剂激活受体α相互作用 （PPARα），表明LFABP可以通过改变这种激活来在全身能量平衡中发挥作用 转录因子。基于这些观察结果，我们的目的是1）确定组织特异性贡献 在全身lfabp中观察到的肠道 - lfabp和肝lfabp到MHO表型 小鼠； 2）确定LFABP是否充当脂质传感器和伴侣，支持脂质的运动 改变信号转导和转录因子活性的配体。拟议的研究将使用 通过CRISPR/CAS9系统生成的有条件敲除（CKO）LFABP小鼠，提供新信息 关于LFABP在控制全身能量稳态中所扮演的角色。