Human Lipoprotein Metabolism: An OverviewCHAPTER 1

Plasma lipoproteins contain a hydrophobic nonpolar lipid core of cholesteryl esters (CE) and triglycerides (TGs) and are surrounded on the surface by a more polar, hydrophilic coat of apolipoproteins, phospholipids, and unesterified cholesterol. The compositions of the lipoproteins ascertain their size and structures. The size and density of lipoprotein are a direct function of neutral lipid content. The largest lipoprotein particles being least dense have the highest ratio of neutral to polar lipids (Table 1).¹ There are five major types of lipoproteins, classified on the basis of their density at which they are isolated, that is, as the high-, low-, intermediate-, and very low-density lipoproteins (HDLs, LDLs, IDLs, and VLDLs, respectively); The least dense and largest lipoproteins are the chylomicrons (CM), which are intestinally derived and composed mainly of dietary lipids and small amounts of protein. HDL appears in two subclasses, HDL2 and HDL3. Lipoprotein metabolism involves the transport of TG from liver and intestine to muscles and adipose tissue, plus the transport of cholesterol both from intestine and liver to peripheral 4tissues, and from periphery back to the liver as well. TGs are the key component of energy transport and metabolism, and cholesterol is a vital component of all cells and essential for steroidogenesis.² Correlations between coronary artery disease and the plasma concentrations of lipoproteins as well as their properties and compositions, have revealed mechanisms that eventually aided diagnosis and provided novel targets for pharmacologic treatment of dyslipidemia and atherosclerosis.¹

Apolipoproteins add structural stability and play a critical role in the recognition of lipoproteins. ApoB-containing lipoproteins include CMs, VLDL, VLDL remnants (also known as IDL), LDL, and lipoprotein(a) [Lp(a)]. ApoB-containing lipoproteins are lipid-rich and play an important role in carrying TGs and cholesterol in the blood. The majority of HDL lipoproteins have both ApoA-I and A-II. ApoA-containing lipoproteins are essential components of reverse cholesterol transport (RCT) and are the initial acceptors of cholesterol from peripheral tissues. HDL lipoproteins are much more complex than VLDL or LDL, and very heterogeneous.³ ApoC and ApoE containing lipoproteins are “conductor” lipoproteins that can orchestrate the lipoprotein metabolism efficiently. Continuous exchange of these two classes of apolipoproteins occurs between HDL and VLDL/LDL particles after meals. ApoC lipoproteins regulate lipoprotein lipase (LPL) activity. The cholesterol efflux in the periphery is determined by ApoE lipoproteins.^3,4 Table 2 illustrates the types and functions of different apolipoproteins.

Lipoprotein metabolism has two pathways to maintain the movement of lipids from diet to blood to cells: (1) The exogenous pathway, and (2) The endogenous pathway.5

More than 90% of dietary lipids are TGs. The remaining consists of cholesterol, CEs, phospholipids, and fatty acids (FAs). TGs are not soluble in the blood and therefore are transported as CMs and VLDL particles.⁵ Following consumption, dietary lipids are digested by lingual and gastric lipase in the stomach. Pancreatic lipase further converts TG to a mixture of 2-monoacylglycerol and free fatty acids (FFAs), while CEs are processed by cholesterol esterase to cholesterol and FFAs. These products are packed with bile salts and fat-soluble vitamins forming mixed micelles which then diffuse into intestinal mucosal cells. Inside the enterocytes, TG is reformed through the re-acylation of the 2-monoacylglycerols by monoacylglycerol acyltransferase and diacylglycerol acyltransferase,⁶ while absorbed dietary cholesterol is esterified by cholesterol acyltransferase to form CE. The TGs and CEs are packaged within CMs, which are involved in the transport of exogenous (dietary) lipids from the intestine to the lymphatic system into the systemic circulation through the exogenous pathway (Fig. 1).⁷ CMs are the largest in diameter with the highest TG content (TG to cholesterol ratio in CM is 8:1). These CMs carry TG and CE to the peripheral tissues including muscles and adipose tissues. Approximately 10–12 hours is required to clear the blood of CMs following a meal. Peak lipidemia is reached in about 3–5 hours. In the plasma, the ApoC-II on the CM surface activates LPL that is present at the capillary endothelial cells.³ By the action of activated LPL, FFAs are released and undergo beta (β)-oxidation to be used for local metabolic needs or stored in the adipocytes. Through the action of cholesterol ester transfer protein (CETP), CM acquires CE from HDL in exchange for TG. Through these metabolic processes, the formation of smaller, cholesterol-enriched particles (chylomicron remnants) occurs. These particles are rapidly removed by the liver. In the lymphatic system, CMs exchange ApoA-I and A-II for ApoC and E from HDL. ApoC is necessary for the activation of the LPL and ApoE is required for the recognition of the CM remnants by the hepatic receptors.^3,86

The first step in VLDL synthesis involves ApoB-100 synthesis on ribosomes attached to the endoplasmic reticulum. An enzyme called “microsomal triacylglycerol transfer protein (MTTP)” assembles triacylglycerols (TAG) and cholesterol with ApoB, E, and a phospholipid. These nascent particles contain more phospholipids and much less unesterified cholesterol in comparison to plasma VLDLs. VLDL is secreted from the liver into the plasma. TAGs form 50–60% of VLDL's weight and are the major fat that is transported from the liver into the blood. It contains a number of apolipoproteins, but ApoB-100 is necessary for its secretion from the liver. The TAG to cholesterol ratio in VLDL is 5:1 on average.³ Alike the process with CM, ApoC, and ApoE are obtained from HDL where ApoC activates LPL that hydrolyzes TG in VLDL liberating FFAs that are taken up by the muscles for energy production or stored in adipose tissues. As with CM, through the action of CETP, VLDL exchange CE for TG with HDL resulting in the formation of relatively TG-depleted IDL which can be resorbed by the liver via the ApoE/remnant receptor or further hydrolyzed by hepatic lipase to form LDL (Fig. 1).⁷ Phospholipid transfer protein (PLTP) mediates the transfer of phospholipids from VLDL to HDL. The main mechanism regulating VLDL secretion and uptake by the liver is under control of the Farsenoid X receptor (FXR) and SREBP-1c transcription factor.⁹

This pathway includes the mobilization of cholesterol from the cells along the arterial wall and the delivery of the cholesterol to the liver in the form of CE. The pathway begins with the secretion of a disk-shaped ApoA-I containing particle by liver and intestine, called nascent HDL. ApoA-I in this nascent HDL particle interacts with the adenosine triphosphate (ATP)–binding cassette (ABC) protein, ABCA1, on the peripheral cells such as macrophages. The ABCA1 protein mediates efflux of free cholesterol (FC) from the intracellular storage pools onto the HDL particle, thereby forming pre-β HDL. Lecithin-cholesterol acyl transferase (LCAT) and its cofactor, ApoA-I esterifies the FC to form CE on the surface of the HDL particle.³ As it circulates, pre-β HDL particles are transformed into a more spherical α-HDL particle that contains CE in its core. Mature α-HDL converts into mature α-HDL subtypes, α-HDL2 and α-HDL3 and continue to receive FC from inside the cells, thus increasing the amount of cholesterol transported to the liver via the CE-rich α-HDL via both direct and indirect pathways. In the direct pathway, CE-rich α-HDL binds to scavenger receptor B1 (SRB1) that facilitates the selective uptake of α-HDL to the liver and excretion in bile. In the indirect pathway, CE-rich α-HDL exchanges CE for TG from the VLDLs and LDLs, a process that is facilitated by CETP. CEs are then taken by hepatocytes through LDL receptors, transformed to bile acids, and finally excreted via the biliary tree.⁸ In physiological states, HDL particles are continuously shifting between larger and smaller particles that aid the transport of cholesterol, TG, and phospholipids between the different lipoproteins and are vital to the initial step of RCT.³ An illustration of RCT is provided in Figure 2.

De novo synthesis and diet are the two sources of cholesterol for the human body. Cholesterol biosynthesis accounts for the majority of serum cholesterol even when individuals are on a high cholesterol diet. Intestinal absorption of cholesterol is the primary mechanism that regulates the contribution of dietary cholesterol to total cholesterol levels.¹⁰ Our body produces around 700 mg of cholesterol daily. Although, any nucleated cell can synthesize cholesterol, the bulk of cholesterol in the blood comes from the liver. Consequently, regulating the capacity of the liver to synthesize or catabolize cholesterol is crucial to determining cholesterol levels in the circulation.

Certain disease conditions interfere with lipid or lipoprotein metabolism pathways, leading to serious disorders. For example, in type 2 diabetes mellitus (T2DM), relative insulin resistance causes underutilization of VLDLs and CMs, ultimately leading to hypertriglyceridemia and increased small-dense LDLs which promotes atherosclerosis.¹² Insulin inhibits the release of FFAs from the adipocytes and suppresses hepatic VLDL production and secretion. These mechanisms come into play in the role of DM as a risk factor for cardiovascular disease (CVD). Additionally, the inability to suppress VLDL-TG kinetics 9has been implicated in the pathogenesis of the nonalcoholic fatty liver disease (NAFLD),¹³ a serious complication that leads to CVD, liver fibrosis, and increases mortality.

Lipoprotein metabolism is an integrated process through which peripheral tissues exchange cholesterol, FAs, and phospholipids, and is mainly organized in the liver. In the fed state, the exogenous pathway predominates, whereas, the endogenous pathway predominates in times of fasting. When there is calorie surplus, lipids are packaged and stored in the adipose tissue. HDL metabolism plays a central role in RCT. These processes are well regulated in healthy states and are pretty abnormal in dyslipidemia. The increased exposure to cholesterol or oxidized lipids favors inflammation in the artery wall, ultimately leading to wall thickening, plaque formation, and rupture. A better understanding of the molecular mechanisms that facilitate lipid metabolism is important for designing appropriate therapies in order to address the CVD risk.