Lipoprotein lipase (LPL) and hepatic triglyceride lipase (HTGL) are two enzymes whose activity is central to the metabolism of triglyceride rich lipoproteins. In humans, a deficiency of either activity is associated with marked abberrations in the clearance and interconversion of lipoprotein particles and produces clinically significant hyperlipidemias. In addition to a functional relationship, there is controversial evidence that these enzymes may be structurally related. However, at present, the nature and extent of this relationship is unclear. This proposal describes a mouse mutant which is the first animal model of primary triglyceride lipase deficiency and the only known system in which both enzyme activities are absent simultaneously. A single mutation, cld(combines lipase deficiency), is apparently responsilble for this lethal condition. Thus, the central aims of this proposal are to characterize the pathophysiology produced by the cld mutation and to gain some insight into the relationship between cld and the expression of LPL and HTGL activities. This proposal includes studies of the identity, structure and composition of the lipoprotein particles which accumulate in cld animals. In addition, hand rearing in conjunction with a synthetic, low fat diet will be tested to prevent lethal hypertriglyceridemia. Routine pathology and clinical chemistry, together with light and electron microscopy will be used to determine the pathophysiological consequences of the cld mutation. The elaboration of both LPL and HTGL activities requires many steps including synthesis of the enzyme protein, posttranslational modification, secretion from the cell, and binding to the capillary endothelial surface. Thus, a genetic defect in any of a number of processed can produce deficiency of enzyme activity. In order to characterize cld, specific antibodies against LPL and HTLG will be produced and used to develop radioimmunoassays or enzyme linked immunosorbant assays. These tools will allow identification and measurement of LPL and HTGL protein present in preparations from cld mice. This will provide insight into the nature if the cld mutation.
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