GLYCEROLIPID METABOLISM IN MICROBODIES

微生物中的甘油脂代谢

基本信息

批准号：
3396459
负责人：
AMIYA K HAJRA
金额：
$ 8.99万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
财政年份：
1979
资助国家：
美国
起止时间：
1979-12-01 至 1994-11-30
项目状态：
已结题

项目摘要

Microbodies, i.e. peroxisomes and microperoxisomes, are ubiquitous catalase-containing subcellular organelles whose biological function is as yet unclear. There are a number of indications that these organelles play a role in cellular lipid metabolism because a number of important lipid-metabolizing enzymes have been described to be present in animal peroxisomes. In our laboratory, we have shown that the key enzymes of the acyl dihydroxyacetone phosphate pathway for glycerolipid biosynthesis are localized in microbodies. The acyl DHAP pathway is the only route through which ether lipids (glycerol ether lipids and plasmalogens) are biosynthesized. This obligatory role of peroxisomes in ether lipid biosynthesis has recently been demonstrated by the discovery of a number of genetic diseases (Zellweger cerebrohepatorenal syndrome (ZS), neonatal adrenoleukodystrophy (neonatal ALD), Refsum disease) in which the tissues of the patients are deficient in both peroxisomes and ether lipids. The major objective of this research proposal is to investigate the interrelationship between microbodies and cellular lipid metabolism. We will pursue our hypothesis that the main function of peroxisomes is to compartmentalize the substrates and enzymes so that the biochemical reactions can proceed and the products of the reactions are utilized in other subcellular compartments for lipid biosynthesis. We will try to develop methods for the preparative isolation of microbodies from different tissues and from cultured human skin fibroblasts. With the purified preparatioN of microbodies we will perform extensive studies of the composition, distribution and topography of different membrane- bound enzymes. We will continue our studies on the effects of hypolipidemic drugs, such as clofibrate, which are known to cause proliferation of peroxisomes on the activities of different enzymes and the metabolite content of microbodies. Detailed studies will be performed on the effects of other physiological parameters such as fasting, feeding a high fat or carbohydrate diet, and administering hormones (which are known to control lipid metabolism) on the activity of peroxisomal enzymes. We will also study in detail the extent and nature of the enzyme defects in the cultured skin fibroblasts from patients suffering from peroxisomal dysfunction such as ZS, neonatal ALD, Refsum disease and Rhizomelic chondrodysplasia punctata. The results of these studies should be useful in both diagnosing the patients and in developing a possible strategy to treat these patients (e.g. dietary ether lipid therapy).

微型生物，即过氧化物酶体和微氧酶体，无处不在含状酶的亚细胞细胞器的生物学功能尚不清楚。有许多迹象表明这些细胞器在细胞脂质代谢中起作用，因为许多重要的脂质代谢酶已经描述存在于动物过氧化物酶体中。在我们的实验室中我们已经证明了酰基二羟基丙酮的关键酶用于甘油脂肪生物合成的磷酸盐途径位于微型生物。酰基DHAP途径是唯一通过乙醚脂质（甘油醚脂质和纤溶酶）是生物合成。过氧化物酶体在醚脂质中的这种强制性作用最近通过发现了生物合成遗传疾病的数量（Zellweger小脑脑脑综合征（ZS），新生儿肾上腺肌营养不良（新生儿ALD），参考疾病）其中患者的组织都缺乏过氧化物酶体和醚脂质。该研究建议的主要目的是调查微型生物与细胞脂质之间的相互关系代谢。我们将追求我们的主要功能的假设过氧化物酶体的底物和酶划分因此，生化反应可以进行以及这些反应用于其他亚细胞隔室的脂质生物合成。我们将尝试为从不同组织和来自培养的人皮肤成纤维细胞。带有纯化制备微型生物，我们将对不同膜的组成，分布和地形结合酶。我们将继续研究低脂肪药物，例如氯纤维抗体，已知会导致过氧化物酶体在不同酶活性上的扩散以及微生物的代谢物含量。详细的研究将对其他生理参数的影响进行此类影响作为禁食，喂养高脂肪或碳水化合物饮食，以及给药激素（已知可以控制脂质代谢）对过氧化物酶体酶的活性。我们也会详细研究酶缺陷的程度和性质患有过氧化物酶体患者的培养的皮肤成纤维细胞功能障碍，例如ZS，新生儿ALD，Refsum疾病和根茎软骨增生性刺激性。这些研究的结果应该是在诊断患者和开发可能的治疗这些患者的策略（例如饮食乙醚脂质治疗）。