The enzyme lipoprotein lipase (LPL) is synthesized in fat cells and then secreted to the extracellular space where it catalyzes the hydrolysis of circulating triglycerides. Although it is well known that the activity of LPL undergoes rapid adaptation with nutritional state, the mechanisms underlying these adaptations are unclear. We have previously demonstrated that refeeding after a 72h fast produces a prolonged overshoot of adipose tissue LPL activity which peaks at day 10 of refeeding. Preliminary data also suggests that LPL secretion is relatively decreased with fat cell enlargement in spontaneously obese rats, although cellular LPL is greater. Rates of LPL synthesis, degradation, activation and secretion in isolated fat cells from rats that have been fasted for 19 or 72h, and then refed for 5 or 10 days, and in fat cells from lean and obese rats will be studied. Rates of LPL secretion will be measured with a modified perifusion technique. This method minimizes the problem of rapid thermal inactivation of enzyme activity that prevents quantitation or studies of the kinetics of LPL release with incubation systems. Specific rates of LPL synthesis and degradation will be measured by biosynthetic labelling with 14C-lysine followed by immunoprecipitation with specific antiserum. In vitro studies will also be carried out to assess the effect on insulin and other hormones on LPL synthesis and secretion. Preliminary studies indicate that preincubation with insulin increases the rate of LPL secretion before an effect on cellular activity. Responsiveness to this insulin effect will be compared in fat cells from rats in different nutritional states. Finally, the subcellular distribution of LPL activity in fat cells will be characterized and possible insulin effects on its distribution studied. This work should provide basic information on the cellular regulation of LPL which is critical to understanding abnormalities of this regulation in obesity and diabetes.
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