Transport And Metabolism

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Solubility of Lipids

Transport of largely hydrophobic lipids through the circulation is achieved in large part by use of aggregates of lipids and protein, called lipoproteins. Principal lipid components of lipoproteins are TG, CH, CE, and PL. Protein constituents, termed apolipoproteins or apoproteins, increase both particle solubility and recognition by enzymes and receptors located at the outer surface of lipoproteins. The major lipoprotein classes are listed in Ta.ble 4.:.,3. (32a). Lipoproteins differ in composition; however, all types feature hydrophilic apoproteins, PL polar head groups, and CH hydroxyl groups facing outward at the water interface, with PL acyl tails and CH steroid nuclei oriented toward the interior of the aggregate. CE and TG molecules form the core of the lipoprotein particle. In this manner, hydrophobic lipids can be internally solubilized and transported within a water medium. Lipoproteins represent a continuous spectrum of particles varying in size, density, composition, and function. Internal transport of lipids can be divided into exogenous and endogenous systems, reflecting lipids of dietary and internal origin, respectively.

Table 4.3 Physical-Chemical Characteristics of the Major Lipoprotein Classes

Exogenous Transport System

The exogenous transport system transfers lipids of intestinal origin to peripheral and hepatic tissues ( Fig 4.4). Such lipids may originate from diet or secretions in the intestine. The exogenous system starts with reorganization in the enterocyte of absorbed FA, 2-MG, lysophospholipids, PL, smaller amounts of glycerol, CH, and phytosterols into molecules more readily packaged within the primary secretory unit, the chylomicron. Chylomicrons are assembled in the enterocyte endoplasmic reticulum membrane in conjunction with the Golgi apparatus. Chylomicron TG are reassembled predominantly via the monoacyl-glycerol pathway. Absorbed FA are activated by microsomal FA-CoA synthase to yield acyl-CoA, then combined sequentially with 2-MG through the action of mono- and diglyceride-acyltransferases. In addition, about 20% of TG resynthesis occurs by the a-glycerophosphate pathway. a-Glycerophosphate, synthesized de novo within the enterocyte from absorbed free glycerol or triose phosphates, combines with two fatty acyl-CoA units to form phosphatidic acid. After dephosphorylation, the 1,2-diglyceride is converted to TG by addition of a further fatty acyl-CoA. Phosphatidic acid is also converted to PL with addition of FA, as is most lysophospholipid entering the enterocyte. The extent to which the phosphatidic acid pathway contributes to TG synthesis is influenced by the PL requirement of the enterocyte for chylomicron structure and assembly. Absorbed free CH is in large part reesterified using fatty acyl-CoA by acyl-CoA cholesterol acyltransferase (ACAT) located in microsomes ( 33).

Synthesis of new lipid appears to be a driving force in assembly and secretion of lipoproteins. Uptake of dietary long-chain fatty acids (LCFA), incorporation into TG by the glycerol-3-phosphate pathway, and assembly of lipoproteins all require fatty acid-binding protein (FABP) ( 34).

Not all FA require chylomicron incorporation and transport. FA less than 14 carbons in length and those containing several double bonds undergo, to a variable degree, direct internal transport via the portal circulation. Fats undergo direct portal transfer either as lipoprotein-bound TG or albumin-bound free (unesterified) FA. Portal transfer delivers FA to the liver faster than chylomicron transit. The FA structure-dependent specificity in these studies has raised questions about whether all FA can be considered equivalent in the context of energy and lipid metabolism. An accumulating body of evidence suggests that consumption of fats containing SCFA associated with portal transit results in higher rates of fat oxidation.

Chylomicrons released from mucosal cells circulate through the lymphatic system and reach the superior vena cava via the thoracic duct. Release into the circulation is followed by TG hydrolysis at the capillary surface of tissues by lipoprotein lipase. Hydrolysis of TG within the core of the chylomicron results in movement of FA into tissues and the subsequent production of TG-depleted chylomicron remnant particles. Chylomicron remnants then pick up CE from high-density lipoproteins (HDL) and are rapidly taken up by the liver.

Endogenous Transport System

The endogenous shuttle for lipids and their metabolites consists of three interrelated components. The first, involving very low-density lipoproteins (VLDL), intermediate-density lipoproteins (IDL), and LDL, coordinates movement of lipids from liver to peripheral tissues. The second, involving HDL, encompasses a series of events that returns lipids from peripheral tissues to liver. The third component of the system, not involving lipoproteins, effects the free FA-mediated transfer of lipids from storage reservoirs to metabolizing organs.

Components of the endogenous lipoprotein system are illustrated in Figure..4.4. The system begins with assembly of VLDL particles, mostly in the liver. Assembly of nascent VLDL starts in the endoplasmic reticulum and depends on the presence of adequate core lipids, CE, and TG. It has been estimated using stable isotope tracers that most TG FA within VLDL is preformed (35, 36). Some VLDL particles may also originate from intestinal tissue. Addition of surface lipids, mainly PL and free CH, occurs in the Golgi apparatus before the particle is secreted.

Following secretion of the VLDL particle into the circulation, a number of interchanges with tissues and lipoproteins occur. A major event is deposition of lipids into peripheral tissues. Hydrolysis of VLDL TG occurs through the action of lipoprotein lipase, an enzyme located on the endothelial side of vessel tissue, which mediates hydrolysis of chylomicron TG. Lipase-generated free FA can be used as energy sources or structural components for lipids, including PL, leukotrienes (LT), and thromboxanes (TXA), or converted back to TG and stored. TG and PL from both chylomicron remnants and LDL are also hydrolyzed by hepatic lipase. When hepatic lipase is absent, large LDL particles and TG-rich lipoproteins accumulate. Through Tg depletion, the VLDL particle is converted to a denser, smaller, and cholesterol-rich, triglyceride-rich lipoprotein (TRL) remnant. High circulatory levels of TRL remnants are associated with progression of coronary artery disease. TRL remnants themselves can be cleared from plasma through hepatic lipoprotein receptors or be converted to smaller LDL. LDL is the major cholesterol-carrying lipoprotein. Although LDL levels are associated with heart disease risk in general, recent evidence suggests that a predominance of smaller, denser LDL particles in the circulation confers an elevated risk of coronary heart disease ( 37). An LDL receptor allows the liver to catabolize LDL. Modified or oxidized LDL can also be taken up by a scavenger receptor on macrophages in various tissues, including the arterial wall.

The second component of the endogenous transport system, perhaps nebulously termed reverse CH transport, involves movement of CH from peripheral tissues to the liver. Since 1975, when Miller and Miller (38) described the protective effect of HDL on atherosclerosis, much work has been undertaken to better understand the structure and function of HDL. HDL particles are highly heterogeneous, with subcomponents originating from both the intestinal tract and liver. It has been proposed that HDL particles participate in reverse CH transport by acquiring CH from tissues and other lipoproteins and transporting it to the liver for excretion. Circumstantial evidence suggests that elevated HDL levels are associated with reduced coronary risk in humans; the link between subnormal HDL levels and higher risk has been established (39).

The third component of the endogenous lipid transport system involves non-lipoprotein-associated movement of free FA through the circulation. These FA, largely products of cellular TG hydrolysis, are secreted by adipose tissue into plasma, where they bind with albumin. Recent evidence suggests that saturated fatty acids (SAFA) and C18:1n-9 are more slowly mobilized than PUFA, at a rate that is independent of their relative proportion in adipose tissue ( 40, 41). Albumin-bound FA are removed in a concentration gradient-dependent manner by metabolically active tissues and used largely as energy sources.

Apoproteins, Lipid Transfer Proteins, and Lipoprotein Metabolism

Interorgan movement of exogenous and endogenous lipids within lipoproteins is not incidental, but coordinated by a series of apoproteins. Apoproteins confer greater water solubility, coordinate the movement and activities of lipoproteins by modulating enzyme activity, and mediate particle removal from the circulation by specific receptors. Indeed, rates of synthesis and catabolism of the major lipoproteins are regulated to a large extent by apoproteins residing on a particular surface that is recognized by specific cellular receptors. Much has been learned about the role of apoproteins through the study of genetic defects and their effects on modification of apoprotein structure and thus lipoprotein function ( 42).

Lipoproteins vary in apoprotein content. Apolipoprotein B (Apo-B) is the major protein contained in chylomicrons, VLDL, IDL, and LDL particles. A larger Apo-B-100 is associated with VLDL and LDL of hepatic origin, while a lower-molecular-weight Apo-B-48 species is found in chylomicrons and intestinally derived VLDL. Apo-B-48 is thought to be generated from the same messenger RNA as Apo-B-100. During apoprotein assembly, hydrophobic Apo-B associates with PL in the endoplasmic reticulum immediately after translation and then requires the presence of adequate core lipid CE and tG. This process of assembly of Apo-B-containing lipoproteins may be influenced by FA composition.

Apoprotein E is synthesized in the liver and is present on all forms of lipoproteins. Apo-E binds both heparin-like molecules (which are present on all cells) and the LDL receptor. Apo-E displays genetic polymorphism; at least three alleles of the Apo-E gene produce six or more possible genotypes, which differ in their ability to bind the LDL receptor. Interactions between Apo-E genotype and CH absorption and synthesis have been suggested.

Most HDL particles contain apoproteins A-I, A-II, A-IV, and C. Apo-A-I and Apo-A-IV are believed to be activators of lecithin:cholesterol acyltransferase (LCAT), an enzyme that esterifies CH in plasma. Apo-A-I also appears to be the crucial structural protein for HDL. Three C apoproteins exist: Apo-C-I, Apo-C-II, and Apo-C-III; each possesses distinct functions and all are synthesized in the liver. Apo-C-II, present in chylomicrons, VLDL, IDL, and HDL, is important in activation of the enzyme lipoprotein lipase, along with Apo-E. Apo-C-III, present on chylomicrons, IDL, and HDL, may inhibit PL action.

Apoproteins play a role in interorgan lipid movement and distribution at several levels. For instance, VLDL are modified by lipoprotein lipase in peripheral tissues to form LDL particles. Apo-C-II, activating lipoprotein lipase, hydrolyzes VLDL and chylomicron TG. It is believed that HDL exchanges Apo-E and Apo-C for Apo-A-I and Apo-A-IV on chylomicrons in the circulation. Apo-E is important in the hepatic clearance of TG-depleted chylomicron remnants.

Apoproteins are critical in the removal of particles from the circulation. LDL is taken up into tissues by two processes, mostly in liver cells but also in adipocytes, smooth muscle cells, and fibroblasts. The first process is receptor dependent and involves the interaction of Apo-B-100 and LDL with specific LDL receptors on cell surfaces. Quantitatively, most LDL receptors exist in the liver ( Fig,.4,4). Postcontact events involve clustering of these receptors in coated pits and LDL internalization. The second process is receptor independent. In contrast to receptor-dependent LDL uptake, receptor-independent transport is nonsaturable and does not appear to be regulated. The rate of receptor-independent transfer is low but increases as a direct function of plasma LDL levels; thus uptake by this pathway can be substantial at high plasma LDL levels.

The LDL receptor is sensitive to both the total amount and unesterified fraction of CH within the cell. Receptor integrity, particularly for LDL, is implicated in the progression of atherosclerosis. Individuals with genetically inherited abnormalities in their LDL receptors have greatly elevated LDL levels because of faulty receptor-apoprotein interactions (42). Likewise, genetic problems with apoprotein structure can result in similar elevations of LDL. CH in LDL particles can undergo chemical modification by oxidation and can then be taken up by macrophage LDL scavenger receptors in an unregulated fashion, potentially resulting in foam cell production and atherogenesis. Higher concentrations of CH also favor formation of b-VLDL, particles that float at a density of less than 1.006 but have b-electrophoretic mobility. b-VLDL can arise from chylomicron remnants or be formed by hepatocytes. These particles interact with LDL receptors on macrophages, depositing large amounts of CE into the macrophage. Substantial increases in CE content convert macrophages to foam cells. LDL receptors on macrophages do not appear to be suppressed as CE concentration increases, unlike those on fibroblasts or smooth muscle.

Formation of HDL also critically depends on apoproteins. Coalescence of PL-apoprotein complexes results in aggregation of Apo-A-I, Apo-A-II, Apo-A-IV, and possibly Apo-E to form nascent HDL particles. These CH-poor, smaller Apo-A-I-containing forms of HDL are heterogeneous in size and can be classified overall as pre-b or discoidal HDL. Subsequently, discoidal HDL changes in size and composition in plasma and extracellular spaces as a result of acquiring free CH from cell membranes of peripheral tissues. HDL-binding proteins have been identified on plasma membranes of cells, including macrophages, fibroblasts, hepatocytes, and adipocytes. Free CH taken up by HDL is esterified by LCAT and moves to the core of the HDL particle. LCAT transfers an sn2-acyl group of PC or phosphatidylethanolamine (PE) to the free hydroxyl residue of CH. Esterification prevents reentry of CH into peripheral cells. Phospholipid transfer protein (PLTP), which provides PC to HDL, also contributes to the compositional shifts in HDL. As HDL becomes enriched with CE, proteins Apo-C-II, and C-III are picked up from other lipoproteins to form three spherical categories of HDL. In order of increasing size and lipid content, these include HDL 3, HDL2a, and HDL2b. Spherical HDL likely go through repeated cycles of size increase and decrease over their circulatory life span of 2 to 3 days.

Spherical HDL can be removed from the circulation and metabolized via two routes. First, HDL 2 can transfer CE to either Apo-B-containing lipoproteins or directly to cells. CH moves from HDL2 via cholesterol ester transfer protein (CETP), which mediates the transfer of CE from HDL2 to VLDL and chylomicrons in exchange for TG. Apo-B-containing particles in turn transport CE to liver. CETP is produced in liver and associates with HDL. As a result of CETP, HDL 2 reconverts to the HDL3 form. Other apoproteins on HDL that play a role in reverse CH transport and can activate LCAT include Apo-A-IV, Apo-C-I, and Apo-E. Secondly, entire particles of HDL 2 can be taken up by LDL receptors and possibly by a separate Apo-E receptor present on hepatocytes.

Actions of HDL other than reverse CH transport may include protection of lipoproteins from oxidative modification, direct removal of CH from atherosclerotic lesions, and a role in the metabolism of eicosanoids (39). HDL can inhibit oxidative modification of LDL in vitro and may contribute to HDL antiatherogenic potential in vivo

Plasma albumin may also be important in reverse CH transport. Through passive diffusion, albumin picks up CH from peripheral cells and passes it to lipoproteins, including HDL and LDL. A large proportion of CH efflux persists in the absence of Apo-A-I, suggesting mainly albumin-dependent shuttling ( 44).

Dietary Factors That Influence Plasma Lipoproteins

Dietary factors profoundly influence lipoprotein levels and metabolism, which in turn alter an individual's susceptibility to atherosclerosis. Dietary fat, CH, fiber, protein, alcohol consumption, and energy balance all have major impact. Classic studies originally revealed that consumption of saturated fats elevated circulating total and LDL CH levels in humans (45). Plasma cholesterol-raising effects of SAFA, particularly myristic (C14:0) and C16:0 acids, are well established. Newer technologies that reduce saturated fat content in dairy products result in lower plasma CH levels when these products are consumed by humans ( 46). The CH-raising effect is believed to occur because the regulatory pool of liver CH is shifted from CE to free CH when hepatocytes become enriched with C14:0 and C16:0 acids. Higher levels of free CH in the liver suppress LDL receptor activity, driving up circulatory levels. Postmeal accumulation of VLDL is more prolonged in individuals consuming diets rich in SAFA than in those consuming diets containing n-6 PUFA (47).

Conversely, metabolic studies show that consumption of n-6 PUFA lowers circulatory CH values; however, epidemiologic data fail to demonstrate any direct protective effect of dietary PUFA on coronary heart disease risk. Consumption of n-3 PUFA is more strongly inversely correlated with the incidence of heart disease. Whether this action is due to lipid lowering or changing eicosanoid-related thrombosis susceptibility has not been firmly established. n-3 PUFA that lower circulating TG levels have only a minor impact on lipoprotein CH levels in humans (48).

Consumption of monounsaturated fats also results in lower CH levels, but to no greater extent than n-6 PUFA consumption. Consumption of trans FA raises LDL and lowers HDL levels in a dose-dependent fashion. It has been suggested recently that dietary trans fat consumption may increase CETP activity, explaining the higher circulatory LDL levels associated with trans fat consumption (49). The role of dietary CH in hyperlipidemia has engendered considerable debate. Within the range of normal CH intakes, changing dietary CH content seems to produce little alteration in circulating CH levels or subsequent metabolism ( 50). Certain individuals demonstrate a hypersensitivity to dietary CH, which may result in a misleading perception of the response to dietary CH within a population overall.

Dietary fiber also influences CH levels. In general, insoluble fibers, such as cellulose, hemicellulose, and lignin from grain and vegetables (see Chapters), have limited effects on CH levels, whereas more soluble forms, such as gums and pectins found in legumes and fruit, possess greater CH-lowering properties. Fiber exhibits CH-lowering action by at least three mechanisms other than simple replacement of hypercholesterolemic dietary ingredients. First, fiber may act as a bile acid-sequestering agent. Second, fiber likely reduces the rate of insulin rise by slowing carbohydrate absorption, thus slowing CH synthesis. Third, fiber may produce SCFA, which are absorbed by the portal circulation and inhibit CH syn-thesis.

Qualitative protein intake may also influence circulating CH levels, since consumption of animal protein leads to higher circulating CH levels than consumption of plant protein. Alcohol intake is somewhat arguably associated with heart disease risk. The relationship between alcohol consumption and CH levels is "J" shaped. At lower levels of intake, wine and spirits (but not beer) produce a more favorable lipid profile: lowering LDL and raising HDL CH values. Further, consumption of excess calories resulting in obesity is associated with higher circulating CH levels. Both CH and TG levels fall during weight loss ( 51). The distribution of excess weight appears to have a stronger association with circulating lipid level than the amount of weight ( 52). In summary, these dietary factors suggest that replacing energy-dense and saturated fat-rich, animal-based foods with those obtained from plant sources is warranted to maintain a desirable profile of circulating lipids.

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