LPL biology and physiology has been covered by excellent reviews, for example see ( ). In short, TG produced in the liver and intestine are packaged into very low density lipoproteins (VLDL) and chylomicrons, respectively. VLDL are directly secreted by the liver into the bloodstream, whereas chylomicrons coming from intestinal absorption are initially transported via the lymph and eventually reach the blood. The TG core within these TG-rich lipoproteins (TRL) is hydrolyzed by LPL, present on the vascular endothelial cells, in the lumen of capillary, releasing FFA and monoacylglycerol (MAG) which are taken up by the peripheral tissues for storage in the form of TG or oxidation for energy generation. (Beigneux et al., 2007; Wang and Eckel, 2009).
LPL is produced by many tissues such as adipose tissue, heart, skeletal muscle, islets and macrophages, where it is anchored to the cell surface exterior via heparan sulfate proteoglycans (Mulder et al., 1992; Sendak and Bensadoun, 1998; Wang and Eckel, 2009). Patients with a genetic mutation in either LPL gene or apoC-II, a specific cofactor for LPL, suffer from hypertriglyceridemia as well as massive hyperchylomicronemia (Wang and Eckel, 2009). LPL activity in different tissues is regulated by mechanisms that are tissue specific, in response to nutritional status and helps in the cellular FFA uptake in these tissues. During fasting, LPL activity is the highest in the oxidative tissues such as skeletal and heart muscles directing FFA from circulating TG towards oxidation. In the fed condition, LPL activity decreases in oxidative tissue and increases in white adipose tissue, thus promoting energy storage (Kersten, 2014; Wang and Eckel, 2009).
Hormonal regulation of LPL also in general follows an inverse relationship between skeletal muscle and adipose tissue. Thus, insulin and thyroid hormone increase the expression of LPL in adipose while reducing that in skeletal muscle, whereas estrogens, testosterone and catecholamines have reverse effects in these tissues (Wang and Eckel, 2009). LPL-interacting proteins LPL activity is modulated by several interacting proteins, including lipase maturation factor 1 (LMF1), glycosylphosphatidylinositol-anchored high-density lipoprotein-binding protein 1 (GPIHBP1), receptor-associated protein (RAP), apolipoprotein A5 (ApoA5), and ANGPTLs 3, 4 and 8 (reviewed recently by Kersten, 2017). LMF1 is an ER resident membrane bound protein, which is needed for proper post-translational maturation and thus activity of LPL protein. Indeed, mutations in LMF1 result in severe hypertriglyceridemia (Wang and Eckel, 2009).
The transport of LPL to its site of action at the luminal surface of capillary endothelium is dependent on GPIHBP1, which binds to LPL in the interstitial spaces and transports it across the (endothelial) cell surface to the capillary lumen (Beigneux et al., 2007; Goulbourne et al., 2014; Horton, 2019; Kersten, 2017). GPIHBP1 deletion causes LPL to accumulate in the interstitial spaces in mice leading to severe hypertriglyceridemia (Beigneux et al., 2007). RAP is another ER-resident protein that functions as a chaperone for LPL posttranslational processing and secretion. It was shown that adipocytes deficient in RAP have defective assembly of LPL, with poor binding ability to plasma membrane and interaction with other binding protein partners (Kersten, 2017; Wang and Eckel, 2009). ApoA5 is known to be a regulator of plasma TG-rich lipoproteins and it is known to directly interact with LPL, and enhance the hydrolysis of TG in a proteoglycan dependent manner (Wang and Eckel, 2009).