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.

项目概要/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。 外源性脂质对代谢活跃的组织有下游影响，例如肝脏和 肝脏和胃肠道中脂质运输和代谢的许多方面都是已知的， 然而，这些组织中脂质的细胞内运输以及运输的后果尚未完全阐明。 据了解，这些研究将重点关注高度表达的肝脏脂肪酸结合蛋白（LFABP）。 传统上，LFABP 被认为是在小肠 (SI) 和肝脏中的一种蛋白质。 我们最近的研究表明，脂质加工是不可或缺的，有助于脂质的摄取和细胞内运输。 证明在高脂肪 (HF) 喂养的小鼠中消除 LFABP (LFABP-/-) 会对身体产生显着影响 尽管 HF 饲喂 LFABP-/-，但与野生型 (WT) 小鼠相比，体重和身体成分有所不同。 小鼠明显肥胖且贪食，它们表现出代谢健康的肥胖表型（MHO）， 迄今为止，在 LFABP 缺失的小鼠中进行了改善运动表现和正常葡萄糖耐量的研究。 仅使用了全局基因敲除小鼠，因此尚不清楚这些小鼠的巨大变化是否是由于 我们最近的研究也证明了 HF 的消融作用。 喂养 LFABP-/- 小鼠的粘膜内源性大麻素 (EC)、2-花生酰甘油和 anandamide，可能部分有助于观察到的全身表型。 已证明 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 可能通过改变该酶的激活而在全身能量平衡中发挥作用。 基于这些观察，我们的目标是 1) 确定组织特异性的贡献。 肠 LFABP 和肝 LFABP 与在全身 LFABP 中观察到的 MHO 表型的关系-/- 小鼠；2) 确定 LFABP 是否充当脂质传感器和伴侣，促进脂质运动 拟议的研究将使用配体来改变信号转导和转录因子的活性。 通过 CRISPR/Cas9 系统生成的条件敲除 (cKO) LFABP 小鼠，提供新信息 LFABP 在调节全身能量稳态中的作用。