There are three main lipids in the blood: cholesterol, phospholipids, and triglycerides. Cholesterol is important for the synthesis of bile acids and steroids and for maintaining the integrity of cell membranes, while phospholipids are a major component of all cell membranes. Triglycerides (TGs) serve as a storable high-energy fuel. In humans, almost 80% of the energy requirements of the heart and liver are fulfilled by oxidation of the long fatty acyl chains present in TGs [1].

Because lipids are poorly soluble in blood plasma, they need to be transported as lipoproteins. Lipoproteins are composed of cholesteryl esters and TGs surrounded by a hydrophilic shell made of phospholipids, unesterified cholesterol, and apolipoproteins. Depending upon the origin of the lipoproteins they differ in size, density, and composition [2,3]. The lipoproteins are generally divided into five major classes. These classes are chylomicrons, VLDL, LDL, intermediate-density lipoprotein (IDL), and high-density lipoproteins (HDL). Each class of lipoprotein serves distinct roles in the lipid metabolism (Figure 1); (i) the large chylomicrons and VLDLs are responsible for the transport and delivery of energy rich TGs, (ii) LDL deposits cholesterol in tissues, and (iii) HDL absorbs cholesterol and transports it back to the liver for degradation and redistribution (Figure 1). The lipoproteins constantly undergo enzymatic processing, exchange of lipids or apolipoproteins, and progressive degradation by lipid unloading. Combined, this network is crucial for lipid homeostasis, and even minor alternations in either of the lipoproteins classes potentially perturbs the entire lipoprotein processing network. LDL and HDL have been found to be important for the development of arteriosclerosis due to their cholesterol cargo. However, studies have shown that elevated plasma triglyceride levels known as hypertriglyceridemia (HTG) is associated with an increased risk of atherosclerosis and CVD [4,5,6]. LPL is responsible for the hydrolysis of the triglyceride in capillaries and thereby transform chylomicrons and VLDL to smaller lipoproteins particles. This process is tightly regulated by a number of proteins that either display a stabilizing, activating, or inhibitory effect of LPL and perturbations of this homeostasis may have anti-atherogenic effects [7,8,9,10,11]. On the other hand, data have shown that when LPL is expressed by macrophages in the vessel wall it displays pro-atherogenic effects [12]. With this in mind, there is a great need to understand the underlining molecular mechanism(s) causing increased triglyceride levels in hypertriglyceridemia and atherosclerosis and map the complex regulation of LPL. This knowledge will likely identify new avenues for lipid lowering strategies that could serve as supplements to the existing interventions (e.g., statins) to help further restraining ASCVD progression.

The central role of LPL in triglyceride hydrolysis was recognized over 60 years ago by the discovery of the enzyme in 1955 [13]. The expression level of LPL is robust in cells and organs with a high oxidative metabolism, but it is also expressed in other tissue types, not related to intravascular lipolysis such as the spleen, testis, lung, kidneys, and brain as well as in macrophages [14]. LPL is a 55 kDa glycoprotein consisting of an N-terminal α/β-hydrolase domain and a C-terminal Polycystin-1, Lipoxygenase, Alpha-Toxin (PLAT) domain (Figure 2). The α/β-hydrolase domain harbors the active site that primarily hydrolyses the sn-1/sn-3 ester bonds of triglycerides, thereby releasing two unesterified fatty acids and a sn-2 monoacylglycerol [15]. The hydrolysis takes place at the luminal face of the capillary endothelium where LPL hydrolyzes the triglycerides within the neutral cores of chylomicrons and VLDLs producing chylomicron remnants and IDLs, respectively (Figure 1) [16]. The released free fatty acids (FFA) can either be used as an energy source or be re-esterified and stored in adipose tissues as triglycerides.