Molecular Physiology of Liver Fatty Acid Transporters

肝脏脂肪酸转运蛋白的分子生理学

• 批准号: 8456208
• 负责人: Andreas Stahl
• 金额: $ 30.43万
• 依托单位: UNIVERSITY OF CALIFORNIA BERKELEY
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-01-15 至 2015-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8456208
• 关键词: Acids; Address; Animals; Bile Acids; Bile fluid; Biological; Cell membrane; Cholelithiasis; Chronic Disease; Complex; Dependovirus; Development; Diabetes Mellitus; Disease; Excretory function; Fat-Soluble Vitamin; Fatty Acids; Fatty Liver; Genetic; Goals; Hepatic; Hepatobiliary; In Vitro; Individual; Insulin; Insulin Resistance; Investigation; Knock-out; Lead; Link; Lipids; Liver; Mediating; Metabolism; Molecular; Nonesterified Fatty Acids; Nucleotides; Obesity; Oligonucleotides; Organ; Organelles; Phenotype; Physiology; Play; Predisposition; Protein Inhibition; Proteins; Public Health; Regulation; Role; Serum; Signal Transduction; Sterols; Symptoms; System; Testing; Tissues; Very Long Chain Fatty Acid; Very low density lipoprotein; absorption; base; bile acid-CoA ligase; blood glucose regulation; cholesterol absorption; diabetic; fatty acid oxidation; fatty acid-transport protein; feeding; improved; in vivo; insulin sensitivity; long chain fatty acid; novel; obesity treatment; overexpression; peroxisome; prevent; protective effect; protein function; protein protein interaction; public health relevance; research study; small hairpin RNA; stable cell line; uptake

DESCRIPTION (provided by applicant): Accumulation of hepatic lipids has been linked to the development of hepatic insulin resistance. Particularly, in obese individuals chronically elevated serum free fatty acids (FFA) and high insulin levels lead to increased FFA uptake by the liver and increased synthesis of lipids resulting in hepatic steatosis. Here we postulate that hepatic FATPs are multifunctional proteins facilitating both protein-mediated fatty acid uptake/activation as well as bile activation, linking hepatic fatty acid and sterol metabolism. We propose that inhibiting liver FATPs may alter inter-organ and intracellular lipid fluxes and therefore influence hepatic steatosis, insulin sensitivity, whole body glucose homeostasis, as well as bile related diseases such as cholelithiasis. We will demonstrate this multifunctional role in vitro and in vivo by determining the interdependence of transport and enzymatic activities of hepatic FATPs and by determining the mechanism by which inhibition of hepatic FATPs can improve hepatosteatosis and other hepatobiliary disorders as well as insulin resistance. To address the biological and therapeutical implications of suppression of hepatic FATPs in vivo, we have developed and implemented adeno-associated virus (AAV) mediated shRNA expression systems, genetic knockout approaches, and anti- sense oligo nucleotide (ASOs) based regiments which will be used to delineate the extend and mechanisms by which inhibition of hepatic FATPs can improve obesity related hepatobiliary disease and insulin sensitivity. Ultimately, our studies will demonstrate whether hepatic FATPs could represent novel targets for the treatment of obesity associated hepatobiliary diseases as well as diabetes.

描述（由申请人提供）：肝脏脂质积累与肝脏胰岛素抵抗的发展有关。特别是，在肥胖个体中，长期升高的血清游离脂肪酸（FFA）和高胰岛素水平导致肝脏对FFA的摄取增加，脂质合成增加，导致肝脏脂肪变性。在这里，我们假设肝脏FATPs是多功能蛋白质，既促进蛋白质介导的脂肪酸摄取/激活，也促进胆汁激活，将肝脏脂肪酸和固醇代谢联系起来。我们认为，抑制肝脏FATPs可能会改变器官间和细胞内脂质通量，从而影响肝脏脂肪变性、胰岛素敏感性、全身葡萄糖稳态以及胆石症等胆汁相关疾病。我们将通过确定肝脏FATPs的转运和酶活性的相互依赖性，以及确定抑制肝脏FATPs可以改善肝骨化病和其他肝胆疾病以及胰岛素抵抗的机制，在体外和体内证明这种多功能作用。为了解决体内抑制肝脏FATPs的生物学和治疗意义，我们开发并实施了腺相关病毒（AAV）介导的shRNA表达系统、基因敲除方法和基于反义寡核苷酸（ASOs）的方案，这些方案将用于描述抑制肝脏FATPs可以改善肥胖相关的肝胆疾病和胰岛素敏感性的范围和机制。最终，我们的研究将证明肝脏FATPs是否可以作为治疗肥胖相关肝胆疾病和糖尿病的新靶点。

项目成果

Evidence for protein-mediated fatty acid efflux by adipocytes.

• DOI: 10.1111/j.1748-1716.2011.02367.x
• 发表时间: 2012-04
• 期刊: Acta physiologica (Oxford, England)
• 作者: Henkin AH;Ortegon AM;Cho S;Shen WJ;Falcon A;Kraemer FB;Lee SJ;Stahl A
• 通讯作者: Stahl A

A biocompatible "split luciferin" reaction and its application for non-invasive bioluminescent imaging of protease activity in living animals.

• DOI: 10.1002/9780470559277.ch140047
• 发表时间: 2014-09-09
• 期刊: Current protocols in chemical biology
• 作者: Godinat, Aurelien;Budin, Ghyslain;Morales, Alma R;Park, Hyo Min;Sanman, Laura E;Bogyo, Matthew;Yu, Allen;Stahl, Andreas;Dubikovskaya, Elena A
• 通讯作者: Dubikovskaya, Elena A

Fatty acid transport proteins, implications in physiology and disease.

• DOI: 10.1016/j.bbalip.2011.09.010
• 发表时间: 2012-05
• 期刊: Biochimica et biophysica acta
• 作者: Kazantzis M;Stahl A
• 通讯作者: Stahl A

Fatty acid transport protein 1 is required for nonshivering thermogenesis in brown adipose tissue.

脂肪酸转运蛋白 1 是棕色脂肪组织中非颤抖产热所必需的。

• DOI: 10.2337/db06-0749
• 发表时间: 2006
• 期刊: Diabetes
• 影响因子: 7.7
• 作者: Wu,Qiwei;Kazantzis,Melissa;Doege,Holger;Ortegon,AngelicaM;Tsang,Bernice;Falcon,Alaric;Stahl,Andreas
• 通讯作者: Stahl,Andreas

Development and validation of a high-throughput screening assay for human long-chain fatty acid transport proteins 4 and 5.

• DOI: 10.1177/1087057110369700
• 发表时间: 2010-06
• 期刊: Journal of biomolecular screening
• 作者: Zhou W;Madrid P;Fluitt A;Stahl A;Xie XS
• 通讯作者: Xie XS