Molecular Mechanisms of Intestinal Fatty Acid Absorption

肠道脂肪酸吸收的分子机制

• 批准号: 7133948
• 负责人: CASEY L MOULSON
• 金额: $ 8.52万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-07-15 至 2009-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7133948
• 关键词: cholesterol; dietary lipid; fatty acid transport; fatty acids; gastrointestinal nutrient absorption; genetically modified animals; homeostasis; immunoprecipitation; laboratory mouse; ligase; metabolomics; nutrition related tag; protein structure; protein structure function; transfection; transport proteins

DESCRIPTION (provided by applicant): The objective of this proposal is to investigate the molecular mechanisms of dietary lipid absorption and the role of fatty acid tranport protein 4 (FATP4), hypothesized to be the dominant small intestine long-chain fatty acid transporter. Because FATP4 null mice die shortly after birth, the role of FATP4 in dietary lipid absorption has not been assessed. Using a transgene expressed exclusively in skin, FATP4 null mice have been rescued and express no FATP4 in the intestine. These mice consume 10% more food per gram body weight than controls, yet manifest reduced serum triglycerides and cholesterol, differences that become more pronounced after consumption of a high-fat diet. These results suggest defective lipid absorption in rescued mutants, which may be partially compensated. The specific aims of this project are to determine the role of FATP4 in dietary fatty acid absorption, cholesterol homeostasis, and lipid processing through in vivo absorption, metabolic, and packaging studies. The necessity of the acyl-CoA synthetase activity of FATP4 in vivo will be investigated using a transgene with an inactive acyl-CoA synthetase domain bred onto the FATP4 null mouse. Finally, oligomerization of FATP4 will be investigated through immunoprecipitation and examination of dominant-negative activity of a mutated FATP4. These studies will advance our understanding of how dietary lipids are absorbed from the intestines and how FATP4 functions in this regard. \ These studies will be conducted at Washington University and will provide the training and necessary skills for the investigator to make the transition to independent research under the supervision of Nicholas Davidson, with additional scientific and career advice provided from an advisory committee. Results from this research will help to understand the mechanisms by which dietary lipids are absorbed from the intestine and may help to understand obesity. Obesity is currently the second leading cause of preventable disease and death in the United States behind cigarette smoking.

描述（由申请人提供）： 本研究的目的是探讨膳食脂肪吸收的分子机制和脂肪酸转运蛋白4（FATP 4）的作用，假设是占主导地位的小肠长链脂肪酸转运蛋白。由于FATP 4缺失小鼠在出生后不久死亡，因此尚未评估FATP 4在膳食脂质吸收中的作用。使用仅在皮肤中表达的转基因，FATP 4缺失小鼠已被拯救，并且在肠中不表达FATP 4。这些小鼠每克体重消耗的食物比对照组多10%，但表现出血清甘油三酯和胆固醇降低，这种差异在高脂肪饮食消耗后变得更加明显。这些结果表明，有缺陷的脂质吸收获救的突变体，这可能是部分补偿。该项目的具体目标是通过体内吸收、代谢和包装研究确定FATP 4在膳食脂肪酸吸收、胆固醇稳态和脂质加工中的作用。将使用具有无活性酰基-CoA合成酶结构域的转基因繁殖到FATP 4缺失小鼠上来研究体内FATP 4的酰基-CoA合成酶活性的必要性。最后，将通过免疫沉淀和检测突变的FATP 4的显性负活性来研究FATP 4的寡聚化。这些研究将促进我们对膳食脂质如何从肠道吸收以及FATP 4在这方面如何发挥作用的理解。\ 这些研究将在华盛顿大学进行，并将为研究者提供培训和必要的技能，以便在Nicholas Davidson的监督下过渡到独立研究，并由咨询委员会提供额外的科学和职业建议。 这项研究的结果将有助于了解膳食脂质从肠道吸收的机制，并可能有助于了解肥胖。在美国，肥胖是仅次于吸烟的第二大可预防疾病和死亡原因。