Regulation of the synthesis, processing and translocation of lipoprotein lipase.

Lipoprotein lipase (LPL) has its physiological site of action at the luminal surface of capillary endothelial cells where the enzyme hydrolyses the triacylglycerol component of circulating lipoprotein particles (Fig. 1), chylomicrons and very low density lipoproteins, to provide free fatty acids and 2-monoacylglycerol for tissue utilization [1-4]. LPL, therefore, plays a primary role in triacylglycerol metabolism and accordingly is widely distributed in the following tissues: adipose tissue (white/brown), heart, mammary gland (lactating), skeletal muscle (red), adrenal, ovary, thoracic aorta, spleen, small intestine, testes, lung, kidney, brain (hippocampus) and liver (neonatal). Free fatty acids supplied by the LPL reaction in white adipose tissue will be reesterified for the storage of energy as triacylglycerols, whereas fatty acids will be oxidized to provide an energy source in the heart and to regulate thermogenesis in brown adipose tissue. In some tissues such as brain, a physiological role for LPL is not yet completely clear. In recent years, the description of the tissue distribution of LPL originally based on determinations of catalytic activity [4] has been complemented by measurements of LPL mRNA by Northern blotting and in situ hybridization [5-14]. In general, adipose tissue, heart and lactating mammary gland have the highest transcriptional and catalytic activity for LPL. Relative LPL catalytic activity and mRNA content in some guinea pig tissues is shown in Table 1. A similar pattern for the distribution of LPL mRNA was observed in rat tissues [12,13]. However, considerable species-dependent variations in tissue LPL have been reported. For example, substantial LPL mRNA was measured in mouse kidney [11], whereas little or no LPL mRNA could be detected in rat and guinea pig kidney [7,12,13]. The endothelium-bound enzyme (Fig. 1) is often referred to as " functional LPL" since displacement of the enzyme by perfusion with heparin [4,15] or inhibition of enzyme activity by antibodies to LPL [16] resulted in marked reduction in the ability of perfused hearts, for example, to degrade lipoproteins. LPL is subject to developmental regulation [13,14]. Although LPL is usually described as an extra-hepatic enzyme, significant LPL activity can be measured in neonatal livers [17]. The capacity for hepatic synthesis of LPL is markedly reduced in adult liver [18]; therefore, LPL activity in adult livers (Table 1) is mainly due to hepatic uptake of the enzyme from the circulation [8]. The predominant cellular location of LPL is not always known in a multi-cellular tissue, and can be influenced by the stage of development. LPL mRNA was low in adult rat brains [13] compared to neonatal rat brains where the strongest hybridization signal was localized to the hippocampus [10]. In the neonatal heart, the majority of LPL activity is present in mesenchymal cells [19], whereas the cardiac myocyte represents the predominant source of LPL in the adult heart [7,20]. LPL activity can be altered in a tissue-specific manner, which is physiologically important because it directs fatty acid utilization according to the metabolic demands of individual tissues so that the degradation of triacylglycerol-rich lipoproteins can be targeted to specific sites. For example, fasting results in a reduction in LPL activity in adipose tissue but an increase in cardiac tissue [21-24]; as a result, fatty acids are diverted away from storage in adipose tissue to meet the metabolic demands of the heart under conditions of caloric deprivation. Cold exposure produces a selective stimulation of LPL in brown adipose tissue [25,26]. Another example is the dramatic increase in mammary gland LPL activity with a corresponding decrease in adipose tissue LPL activity during lactation [4,27] so that circulating triacylglycerols are preferentially utilized for milk synthesis. Thus, LPL has a pivotal role in total body lipid metabolism. The regulation of LPL is also important in some clinical disorders of lipid metabolism such as obesity where fat cell LPL activity is markedly elevated [2,28]. The most unique characteristic of LPL is the stimulation of enzyme activity by apolipoprotein CII [1,29]. Thus, circulating