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

项目摘要/摘要 膳食脂肪的质量和数量对人类健康的许多方面都很重要。摄取 外源性脂肪对新陈代谢活跃的组织有下游影响，如肝脏和 胃肠道(GI)。肝脏和胃肠道中的脂质运输和代谢的许多方面都是已知的， 然而，脂类在这些组织中的细胞内运输以及这种运输的后果并不完全 明白了。这些研究将集中在高表达的肝脏脂肪酸结合蛋白(LFABP)上 在小肠(SI)和肝脏中。传统上，LFABP被认为是一种蛋白质 为脂质加工所必需的物质，有助于脂质的摄取和细胞内转运。我们最近的研究表明 证明消融LFABP(LFABP-/-)对高脂(HF)喂养的小鼠有显著的影响 体重和身体成分与野生型(WT)小鼠相比。有趣的是，尽管HF喂养了LFABP-/- 小鼠明显肥胖和过度吞噬，它们表现出代谢健康的肥胖表型(MHO)， 改善运动能力和正常的糖耐量。到目前为止，在LFABP基因缺失小鼠身上进行的研究 只使用了全局基因敲除小鼠，因此尚不清楚这些小鼠的戏剧性变化是否由于 消融肠、肝或两种组织中的LFABP。我们最近的研究也证明了HF 喂饲LFABP-/-小鼠的粘膜内源性大麻素(ECs)、2-花生四烯基甘油和 这可能在一定程度上导致了观察到的全身表型。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)，提示LFABP可能通过改变这种激活而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)确定特定组织的贡献 肠道-LFABP和肝脏-LFABP与全身LFABP中观察到的MHO表型-/- 2)确定LFABP是否作为脂质感受器和伴侣，促进脂质的运动 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系统产生的条件性基因敲除(CKO)LFABP小鼠，提供了新的信息 论LFABP在调节全身能量平衡中的作用。

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.