Peroxisomes and microperoxisomes (microbodies) are ubiquitous catalase-containing subcellular organelles whose function in tissues is as yet unknown. There are a number of indications that these organelles play a role in cellular metabolism of lipids. For example, results from our laboratory have shown that some of the enzymes for glycerolipid biosynthesis are localized in microbodies. In higher animals glycerolipids are synthesized either via glycerophosphate or via acyl dihydroxyacetone phosphate. Acyl dihydroxyacetone phosphate has been also shown to be a requisite precursor of all glycerol ether lipids (alkly glycerol ethers and plasmalogens). We have found that the key enzymes of the acyl dihydroxyacetone phosphate pathway for glycerolipid biosynthesis are localized in the rat, mouse and guinea pig liver peroxisomes. The major objective of this research proposal is to investigate the interrelationship between microbodies and cellular lipid metabolism. We will pursue our hypothesis that peroxisomes are primarily involved in supplying the metabolic intermediates to other cellular compartments for lipid biosynthesis. Methods will be developed for the preparative isolation of peroxisomes from liver and kidney and microperoxisomes from developing brain, adrenal glands and gonads. With the purified preparations of microbodies we will perform extensive studies of their enzyme composition and metabolites content. The distribution of the enzymes in microbodies (e.g. membrane-bound or soluble or present in the core) of different tissues and the topography of the membrane-bound enzymes will be studied. We will continue our studies of the effects of hypolipidemic agents to develop a more detailed picture of the changes which take place in peroxisomal enzymes and metabolic intermediates. These agents, such as clofibrate, are known to cause a proliferation of liver peroxisomes and change the activity of a number of enzymes in liver. In addition, detailed studies will be performed on the effects of other physiological parameters such as fasting, feeding a high fat or high carbohydrate diet and administering hormones (which are known to control lipid metabolism) to animals, on the activity of peroxisomal enzymes. The results of these studies should be useful in delineating the physiological function of microbodies in tissues.
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