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).
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