Lipoprotein lipase (LPL) is a multifunctional enzyme produced by and studied in many tissues, including adipose tissue, cardiac and skeletal muscle, islets, and macrophages. After synthesis by parenchymal cells, the lipase is transported to the capillary endothelium, where it is rate-limiting for the hydrolysis of the triglyceride (TG) core of the circulating TG-rich lipoproteins, chylomicrons, and very low density lipoproteins (VLDL). The reaction products, fatty acids and monoacylglycerol, are in part taken up by the tissues locally, where they are processed in a tissue-specific manner, e.g., stored as neutral lipids (TG > cholesteryl esters[CE]) in adipose tissue, oxidized or stored in muscle, or as CE/TG in foam cells in macrophages. LPL is regulated in a tissue-specific manner. In adipose tissue, LPL is increased by insulin and meals but decreased by fasting, whereas muscle LPL is decreased by insulin and increased by fasting. In obesity, adipose tissue LPL is increased; however, the insulin dose-response curve is shifted to the right. After weight reduction and stabilization of the reduced obese state, adipose tissue LPL is increased, as is the response of the enzyme to insulin and meals. In skeletal muscle, insulin does not stimulate LPL nor is the enzyme activity changed in obesity; however, after weight reduction, LPL in skeletal muscle is decreased by 70%. These tissue-specific changes in LPL set the stage for lipid partitioning to help explain the recidivism of obesity. To examine this divergent regulation further, transgenic and knockout murine models of tissue-specific LPL expression have been developed. Mice with overexpression of LPL in skeletal muscle develop TG accumulation in muscle, develop insulin resistance, are protected from excessive weight gain, and increase their metabolic rate in the cold. When placed onto the LPL knockout and leptin deficient background, overexpression of LPL using an MCK promoter reduces obesity. Alternatively, a deletion of LPL in skeletal muscle reduces TG accumulation and increases insulin-mediated glucose transport into muscle but leads to lipid partitioning to other tissues, insulin resistance, and obesity. In the heart, loss of LPL is associated with hypertriglyceridemia and a greater utilization of glucose, implying that free fatty acids are not a sufficient fuel for optimal cardiac function. LPL is also produced in the brain, and that’s where the “story gets even more interesting.” We have just created mice with a neuron-specific deletion of LPL (NEXLPL−/−) using cre recombinase driven by the helix-loop-helix nuclear transcription factor NEX promoter. By 6 months of age, NEXLPL−/− mice weigh 50% more than their litter mates. This phenotype provides convincing evidence that lipoprotein sensing occurs in the brain and is important to energy balance and body weight regulation. Overall, LPL is a fascinating enzyme that contributes in a pronounced way to normal lipoprotein metabolism, tissue-specific substrate delivery and utilization, and to the many aspects of metabolism that relate to cardiovascular disease, including energy metabolism, insulin action, body weight regulation, and atherosclerosis.
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