DISORDERED FATTY ACID METABOLISM

脂肪酸代谢紊乱

• 批准号: 3154358
• 负责人: KOU-YI TSERNG
• 金额: $ 7.93万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1985
• 资助国家: 美国
• 起止时间: 1985-07-01 至 1988-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3154358
• 关键词: carboxylate; chemical structure function; epoxides; fatty acid metabolism; gas chromatography; human tissue; inborn metabolism disorder; liver cirrhosis; mass spectrometry; obesity; oxidation; unsaturated fatty acids; uremias; urinalysis; valproate

Hypothesis: Disordered fatty acid metabolism as a result of inborn errors or other pathophysiological conditions (such as diabetes, uremia, etc.) is related to the endogenous production of unsaturated short chain fatty acids. These acids are derived from dehydrogenation of saturated short chain fatty acids and undergo oxidation to an epoxide intermediate. In the normal environment, these epoxides are detoxified by hydration to non-toxic polyhydroxy- carboxylic acids. Whereas, in disorders, as a result of increased production or decreased hydration, the epoxides accumulate and act as inhibitor to enzymes responsible for fatty acid oxidation. Methods: In fasting metabolism and inborn errors of fatty acid metabolism, a number of carboxylic acids, possibly derived from unsaturated short chain carboxylic acids, are found to be significantly elevated. Studies are proposed to elucidate the role of epoxides in the pathogenesis of disordered fatty acid metabolism. The metabolic conversion and fatty acid oxidation inhibition of 2-butenoic, hexa-2,4-dienoic, unsaturated short chain dicarboxylic acids, as well as their epoxides, will be investigated in the rats. Substantial efforts will be devoted to the elucidation of structures of a number of unknown urinary metabolites found in disordered fatty acid metabolism. Model studies using fatty acid oxidation inhibitors, such as hypoglycin, 4-pentenoic acid, valporic acid, and tetradecylglycidic acid, will be compared with data obtained from potential endogenous metabolic toxins (unsaturated short chain fatty acids and their epoxides). Structure-activity relationship of 2,3-substitured oxirane carboxylic acids toward fatty acid oxidation inhibition will be investigated. As a long term goal, we hope to elucidate the toxic mechanisms of different variants of disordered fatty acid metabolism.

假设：先天性缺陷导致脂肪酸代谢紊乱 或其他病理生理状况（如糖尿病、尿毒症等）是 与内源性不饱和短链脂肪酸的产生有关 acids. 这些酸是由饱和的短链脱氢而得的。 链脂肪酸并经历氧化成环氧化物中间体。 在 在正常环境下，这些环氧化物通过水合作用解毒， 多羟基羧酸 然而，在混乱中，由于 增加产量或减少水合作用，环氧化物积累， 作为脂肪酸氧化酶的抑制剂。 方法：在空腹代谢和先天性脂肪酸代谢缺陷方面， 许多羧酸，可能衍生自不饱和短链 羧酸，被发现是显着升高。 研究是 建议阐明环氧化物在发病机制中的作用， 脂肪酸代谢紊乱 代谢转化与脂肪酸 2-丁烯酸、己-2，4-二烯酸、不饱和短链的氧化抑制 链二羧酸，以及它们的环氧化物，将被研究 在老鼠身上。 我们将致力于阐明 一些未知的尿液代谢物的结构，发现在无序的 脂肪酸代谢 使用脂肪酸氧化的模型研究 抑制剂，如低甘氨酸、4-戊烯酸、戊烯酸，和 十四烷基缩水甘油酸，将与从潜在的 内源性代谢毒素（不饱和短链脂肪酸及其 环氧化物）。 2，3-取代环氧乙烷的构效关系 羧酸对脂肪酸氧化的抑制作用， 研究了 作为一个长期目标，我们希望阐明毒性 脂肪酸代谢紊乱的不同变体的机制。