Lipids, Sterols, and Their Metabolites1



Lipids, Sterols, and Their Metabolites1


Peter J. H. Jones

Todd Rideout





HISTORICAL INTRODUCTION

Evans and Burr, in 1927, were first to demonstrate that a deficiency of fat severely affected both growth and reproduction of experimental animals despite the addition to the diet of fat-soluble vitamins A, D, and E. They suggested that fat contained a new essential substance termed vitamin F. The work of the same investigators in 1929 first demonstrated the nutritional importance of specific lipid components in fat. Weanling rats fed a fat-free diet showed impaired growth, scaly skin, tail necrosis, and increased mortality—conditions that were reversed by feeding linoleic acid (C18:2n-6). The same authors described impaired fertility and increased water consumption as additional symptoms of a deficiency of either C18:2n-6 or α-linolenic acid (C18:3n-3). Subsequently, the term essential fatty acids (EFAs) was coined by Burr and Burr for those fatty acids (FAs) not synthesized in mammals and for which deficiencies could be reversed by dietary addition of specific FAs.

Arachidonic acid (C20:4n-6), also determined to be an EFA in 1938, was found to be approximately three times as effective as C18:2n-6 in relieving EFA deficiency (EFAD) symptoms. C18:2n-6 was shown to undergo biotransformation to C20:4n-6; thus, C18:2n-6 was judged to be the primary unsaturated EFA required by animals in the diet. Although various researchers were able to generate EFAD in a variety of species by feeding EFAdeficient diets, only in 1958 was EFAD first described in humans. Infants fed a milk-based formula diet lacking in EFAs showed severe skin symptoms that were alleviated by the addition of C18:2n-6.

In human adults, EFAD was subsequently described as a consequence of parenteral nutrition in which fat-free glucose solutions were continuously infused. The resulting skin rashes and low plasma polyunsaturated FA (PUFA)
concentrations were reversed by infusion of intravenous emulsions containing C18:2n-6. Holman et al (1) in 1982 reported the first example of deficiency symptoms attributed to C18:3n-3 deficiency in a 6- year-old girl maintained parenterally for 5 months on a safflower oil-based emulsion rich in C18:2n-6. Neuringer et al (2) in 1984 demonstrated C18:3n-3 deficiency in the offspring of Rhesus monkeys who showed a loss in visual activity. C18:3n-3 deficiency was also described in patients who had received 0.02% to 0.09% of calories as n-3 FAs via gastric tube feeding over a period of 2.5 to 12 years (3). The scaly dermatitis and depressed concentrations of n-3 FAs in plasma and erythrocytes of the patients were alleviated with supplementation of C18:3n-3.


CHEMISTRY AND STRUCTURE

Fats and lipids are defined generally as a class of compounds soluble in organic solvents such as acetone, ether, and chloroform. Fats and lipids vary considerably in size and polarity, ranging from hydrophobic triglycerides (TGs) and sterol esters to more polar phospholipids (PLs) and cardiolipins. Dietary lipids also include cholesterol (CH) and phytosterols. Unlike other macronutrient classes, the nonwater miscibility of lipids necessitates their specialized processing during digestion, absorption, transport, storage, and utilization—a requirement that distinguishes them from other dietary macronutrients.


Triglycerides and Fatty Acids

TGs, or triacylglycerols, make up by far the largest proportion of dietary lipids consumed by humans. A TG is composed of three FAs esterified to a glycerol molecule in one of three stereochemically distinct bonding positions named sn-1, sn-2, and sn-3. Variations in the type of FA and their bonding pattern to glycerol further increases the heterogeneity of TG composition. For most dietary oils, approximately 90% of the TG mass consists of FAs, generally nonbranched hydrocarbon chains with an even number of carbon atoms ranging in number from 4 to 26 (4). Very-long-chain FAs (VLCFAs) occur in brain and specialized tissues such as retina and spermatozoa (5, 6). Adipose tissue contains FAs of varying lengths.

In addition to differences in chain length, FAs vary in the number and position of double bonds along the hydrocarbon chain. Major FAs are given in Table 4.1. Systems for identifying the position of double bonds along the hydrocarbon chain entail counting carbons from either end of the FA molecule. The less common “Δ” system counts double bonds from the carboxyl end of the fatty acyl chain. More commonly used is identification of the position of the first carbon of a double bond relative to the methyl terminus of the F, termed “n” or “omega” to indicate distance of the first bond along the carbon chain. A monounsaturated FAs (MUFAs) must be at least 12 carbon atoms in length, typically with the double bond at the n-9 or n-7 position. Addition of further double bonds produces a PUFA. Each subsequent double bond almost invariably occurs three carbon atoms farther along the carbon chain from the bond preceding it. Therefore, the number of double bonds within an FA is restricted depending on its chain length, but it will not exceed six. FAs of 18 carbon atoms or greater that possess more than a single double bond will contain the first bond of their series only at the n-9, n-6, or n-3 position. For a 16-carbon atom FA, the first double bond may be located at the n-7 position.








TABLE 4.1 NAMES AND CODES OF FATTY ACIDS



















































































































COMMON NAME


GENEVA NOMENCLATURE


CODE


Butyric acid


Butanoic acid


C4:0


Caproic acid


Hexanoic acid


C6:0


Caprylic acid


Octanoic acid


C8:0


Capric acid


Decanoic acid


C10:0


Lauric acid


Dodecanoic acid


C12:0


Myristic acid


Tetradecanoic acid


C14:0


Palmitic acid


Hexadeconoic acid


C16:0


Stearic acid


Octadecanoic acid


C18:0


Palmitoleic acid


9-Hexadecaenoic acid


C16:1, n-7 cis


Oleic acid


9-Octadecaenoic acid


C18:1, n-9 cis


Elaidic acid


9-Octadecaenoic acid


C18:1, n-9 trans


Linoleic acid


9,12-Octadecadienoic acid


C18:2, n-6,9 all cis


α-Linoleic acid


9,12,15-Octadecatrienoic acid


C18:3, n-3,6,9 all cis


γ-Linolenic acid


6,9,12-Octadecatrienoic acid


C18:3, n-6,9,12 all cis


Columbinic acid


5,9,12-Octatrienoic acid


C18: n-6 cis, 9 cis, 13 trans


Arachidic acid


Eicosanoic acid


C20:0


Behenic acid


Docosanoic acid


C22:0


Eicosenoic acid


11-Eicosenoic acid


C20:1, n-9 cis


Erucic acid


13-Docosaenoic acid


C22:1, n-9 cis


Brassidic acid


13-Docosaenoic acid


C22:1, n-9 trans


Nervonic acid


15-Tetracosaenoic acid


C24:1, n-9 cis


“Mead” acid


5,8,11-Eicosatrienoic acid


C20:3, n-9,12,15 all cis


Dihomo-γ-linolenic acid


8,11,14-Eicosatetraenoic acid


C20:3, n-6,9,12 all cis


Arachidonic acid


5,8,11,14-Eicosatetraenoic acid


C20:4, n-6,9,12,15 all cis


Timnodonic acid


5,8,11,14,17-Eicosapentaenoic acid


C20:5, n-3,6,9,12,15 all cis


Clupanodonic acid


7,10,13,16,19-Docosapentaenoic acid


C22: n-3,6,9,12,15 all cis


Docosahexaenoic acid


4,7,10,13,16,19-Docosahexaenoic acid


C22:6, n-3,6,9,12,15,18 all cis



The dietary essentiality of an FA depends on the position of the first double bond from the methyl terminus. During de novo FA formation by human biosynthetic enzymes, no double bonds are formed at any position closer to the methyl end than n-9. For this reason, FAs with double bonds at the n-6 and n-3 positions are, as individual classes, considered to be essential in the diet. These EFAs must therefore be obtained from plants or other organisms that possess enzymatic pathways for their construction. Although mammalian tissues contain four families of PUFAs (n-3, n-6, n-7, and n-9), only those of n-6 and n-3 classes are essential to the diet. All other FAs can be synthesized by humans from alternative sources of dietary energy.

Double bonds in dietary fats occur most commonly in the cis configuration. Trans bonds occur as a result of hydrogenation, the process used to increase oil stability, and through microbial metabolism in ruminants. Trans bonds reduce internal rotational mobility of the fatty acyl chain and are less reactive to electrophilic addition such as halogenation, hydration, and hydrogenation (7, 8). Most dietary trans FAs are monoenes, 18 carbons in length. The major trans FA, elaidic acid (C18:1n-9 trans), has a melting point of 44°C versus 13°C for oleic acid (C18:1n-9). Trans bonds are also found in FAs containing more than a single double bond. An example is conjugated linoleic acid, which contains both a cis and a trans double bond separated by only two, instead of three, carbon atoms.


Phospholipids

Limited quantities of dietary lipids occur as PLs. PLs are distinct from TGs in that they contain polar head groups that confer amphipathic properties to the molecule. PLs are insoluble amphiphiles with a hydrophilic, often zwitterionic (containing both a positive and a negative charge) head group and hydrophobic tails composed of two longer chain FAs. These head groups are attached to the primary glycerol moiety via phosphate linkages. Polar head groups vary in size and charge and include inositol, choline, serine, ethanolamine, and glycerol.


Sterols

CH, formed of a steroid nucleus and branched hydrocarbon tail, is found in the diet both in free form and esterified to FAs. CH is found only in foods of animal origin; plant oils are free of CH. Plant materials do, however, contain phytosterols, compounds that are chemically related to CH. Common dietary phytosterols are listed in Figure 4.1. Phytosterols differ in their chemical sidechain configuration and steroid ring-bonding pattern. Most common dietary phytosterols include β-sitosterol, campesterol, and stigmasterol. The Δ-5 hydrogenation of these phytosterols forms saturated phytosterols, which includes campestanol and sitostanol (stanols), that are found in very small amounts in normal diets but can be commercially produced. Plant sterols and stanols are often deliberately esterified to FAs such as C-18:2 n-6 and n-3 FAs to improve their solubility and bioavailability.






Fig. 4.1. Molecular structure of the more important sterols in food (side chains only are shown for the bottom four structures).


DIETARY CONSIDERATIONS

The fat intake of average North Americans represents 35% to 40% of total calories consumed (9, 10). More than 95% of the total fat intake is as TGs, with the remainder occurring in the form of PLs, free FAs, CH, and plant sterols. The total quantity of dietary TGs in the North American diet thus amounts to approximately 80 to 130 g/day. In addition to dietary intake, lipids enter the gastrointestinal tract both via release from mucosal cells and in bile and through bacterial contributions.

In almost no other instance can food choice influence nutrient composition as much as in the case of fats.
As dietary TGs vary widely in FA composition, so does FA consumption (Table 4.2). Large differences exist in the FA composition of oils from both plant and animal sources, largely because of genetic and environmental factors. In the case of animal fats, the composition of the feed also influences the final FA composition. As noted later, these factors influence the FA composition of tissues.








TABLE 4.2 AVERAGE TRIGLYCERIDE FATTY ACID COMPOSITION OF IMPORTANT EDIBLE FATSa





































































































































































































































































FOOD (100 g)


AVERAGE FAT (%)


AVERAGE FATTY ACID COMPOSITION


SATURATED


MONOUNSATURATED AND POLYUNSATURATED


TOTALb


16:0


18:0


18:1


18:2


18:3


20:4


Milk (cow) 3.25%


4


3


0.8


0.4


0.8


0.12


0.08


Butter


81


51


22


10


20


3


0.3


Lard (pig)


100


39


24


14


41


10


1


Porkc


7


2.3


1.5


0.7


3


0.6


0.03


0.08


Tallow


100


50


25


19


36


3


0.6


Beefd


9


3


2


1


4


0.3


0.05


0.04


Chickene


16


3.3


3


0.6


6


3


0.1


Egg


10


3 2


0.8


4


1


0.03


0.1


Turkeyf


2


0.3


0.3


0.08


0.4


0.3


0.01


0.02


Sesame oil


100


14


9


5


39


39


0.3


Soybean oil


100


15


11


4


23


51


7


Corn oil


100


8


5


2


57


23


6


Sunflower seed oil


100


9


4


4


57


29


0


Olive oil


100


14


11


2


7


10


0.8


0


Cottonseed oil


100


26


23


2.3


17


52


0.2


0.1


Safflower oil


100


6.2


4.28


2


14


75


Palm oil


100


49


44


4


37


9


0.2


Coconut oil


100


87b


8


3


6


2


Palm kernel oil


100


82b


8


3


1


2


Canola oil


100


7


4


2


62


19


9


High oleic canola oil


100


7


3


2


70


15


23


Cashew nut


44


8


4


3


24


8


0.06


Walnut


65


6


4


2


9


38


9


Herring (Atlantic)


9


2


1


0.1


2


0.1


0.1


0.06


Salmon (Atlantic)


13


3


2


0.5


3


1


0.2


0.09


aThe figures given are approximations because climate, species, and fodder composition, for example, cause great variations.


b The balance of saturated fatty acids is formed by fatty acids with chain lengths of less than 12 (butter 14%) and 12 and 14 (butter 16%, coconut and palm kernel 65% to 70%).


c Pork, fresh, loin, center rib (chops or roasts), bone-in, separable lean and fat, raw.


d Beef, bottom sirloin, tri-tip roast, separable lean and fat, trimmed to 0″ fat, all grades, raw.


e Chicken breast tenders, uncooked.


f Turkey breast meat.


Data from US Department of Agriculture. National Nutrient Database. Available at: www.ars.usda.gov/ba/bhnrc/ndl. Accessed May 31, 2011, with permission.


Intake of trans FAs in the North American diet has not been firmly established, but it appears to range from 2% to 7% of total energy intake (8, 11), whereas the American Heart Association recommends limiting trans fats to less than 1% of energy (12, 13). Amounts of trans FAs in the diet have been declining over past decades, partly as the rise in vegetable fat consumption has been counterbalanced by a decrease in the trans FA content of many foods made with vegetable fat (7).

The dietary contribution of CH varies significantly across foods. Typically, North Americans consume 250 to 700 mg of CH each day, and the larger proportion of this amount is esterified to FAs. Reduction of dietary CH levels can readily be achieved through exclusion of animal fats and eggs from the diet. North American diets typically contain approximately 250 mg/day of plant sterols, and vegetarian diets contain larger amounts (14).


DIGESTION AND ABSORPTION


Digestion in the Mouth and Esophagus

Digestion of dietary lipids involves a series of specific processes enabling absorption through the water-soluble environment of the gut. Digestion begins in the oral cavity with the processes of salivation and mastication. Lingual lipase, released from the serous glands of the tongue with saliva, commences the hydrolysis of free FAs from TGs at the sn-3 position. Hydrolysis continues into the stomach, where gastric lipase digests lipids and prefers TGs containing short-chain FAs (SCFAs). The composition of fat entering the upper duodenum is approximately 70% TGs, with the remainder a mixture of partially digested hydrolysis products.



Intestinal Digestion

Intestinal digestion requires bile salts (BSs) and pancreatic lipase. BSs, PLs, and sterols are the three principal lipid components of bile—the emulsifying fluid produced by the liver. Primary BSs, defined as those synthesized directly from hepatic CH, include the trihydroxy and dihydroxy BSs, namely cholate and chenodeoxycholate, respectively. Secondary BSs, including deoxycholate and lithocholate, are produced from primary BSs via bacterial conversion on cholate and chenodeoxycholate in the large intestine.

Pancreatic lipase, the principal enzyme of TG digestion, acts to hydrolyze ester bonds at sn-1 and sn-3 positions (Fig. 4.2). BSs inhibit lipase activity through displacement of the enzyme from its substrate at the surface of the lipid droplet. Colipase, also a pancreatic protein, reverses BS inhibition on pancreatic lipase by binding lipase and ensuring its adhesion to the lipid droplet. Then, through its affinity to BSs, PLs, and CH, colipase facilitates shuttling of hydrolysis products monoglycerides (MGs) and free FAs from the lipid droplet into the BS-containing micelle. FAs linked at the sn-2 position of MGs, PLs, and cholesteryl ester (CE) are resistant to hydrolysis by lipase. The action of pancreatic lipase is extremely rapid, and MGs and free FAs are produced faster than their subsequent incorporation into micelles (15).

Micellar solubilization of the products of fat hydrolysis results from the amphipathic actions of BSs and PLs, which are secreted in bile at a ratio of approximately 1:3. CH is present in bile only in the unesterified form, which is the major sterol form (16). The polar terminus of BSs orients itself toward the water milieu of the chyme, whereas the nonpolar ends containing hydrocarbon groups face the center of the micelle. BSs and PLs naturally aggregate such that the nonpolar termini form a hydrophobic core. The incorporation of MGs into the micelle increases the ability of the particle to solubilize free FAs and CH. BS micelles generally possess the highest affinity for MGs and unsaturated long-chain FAs (LCFAs) (17). Both diglycerides (DGs) and TGs have limited incorporation into micelles. On formation, mixed micelles containing FAs, MGs, CH, PLs, and BSs migrate to the unstirred water layer adjacent to the surface of the enterocyte brush-border membrane.


Absorption

The process of lipid absorption appears to occur in large part through passive diffusion. Micelles containing fat digestion products exist in dynamic equilibrium with each other; the peristaltic, churning action of the intestine maintains a high frequency of intermicellar contact. This contact results in partitioning of constituents from more highly populated micelles to less populated micelles, with consequent equalization of the overall micellar concentration of digestion products. Thus, during digestion of a bolus of fat, micelles evenly accrue digestion products. The 2-MGs and free FAs are released through the action of pancreatic lipase until the saturation capacity of the micelles is reached.

The penetration of micelles across the unstirred water layer bordering the intestinal mucosal cells represents the first stage of absorption. Micelles, but not lipid droplets, approach and enter this water layer selectively for two reasons: first, micelles are much smaller (30 to 100 Å) particles than emulsified droplets of fat (25,000 + 20,000 Å); and second, the hydrophobic nature of the larger lipid droplet results in reduced solubilization at the site of the unstirred water layer.






Fig. 4.2. Transport hypothesis of fatty acids and 2-monoglycerides through lipase-mediated hydrolysis, micellar transfer, and cellular uptake stages.


Transport of micellar products across the unstirred water layer into the enterocyte occurs as illustrated in Figure 4.2. The digestion products shuttle from the micelles across the unstirred water layer and create a chain reaction effect. This action hinges on the lower cellular concentration of digestion products at the enterocyte. Intestinal FA-binding proteins (FABPs) assist in transmucosal shunting of digestion product FAs, and possibly MGs and BSs. Elevated FABP activity in the distal bowel has been shown to be associated with higher FA absorption (18).

The overall efficiency of fat absorption in human adults is approximately 95%. However, the qualitative nature of the dietary fat influences overall efficiency (19). Evidence also suggests that as FA chain length increases, absorption efficiency decreases. Similarly, the positional distribution of FAs on dietary TGs is an important determinant of the eventual efficiency of absorption. When octanoate, palmitate, or linoleate were substituted at different sn positions on a TG molecule, the positional distribution altered characteristics of digestion, absorption, and lymphatic transport of these two FAs (20, 21). The natural tendency of C16:0 to be present in the sn-2 position in breast milk may therefore explain the high digestibility of this milk fat. FAs with chain lengths less than 12 carbon atoms are also absorbed passively by the gastric mucosal boundary and taken up by the portal vein (22).

Micellar BSs are not absorbed with fat digestion products, but rather are taken up further along the gastrointestinal tract. Passive intestinal absorption of unconjugated BSs occurs throughout the small intestine and colon. Active transport components predominate in the ileum and include the brush-border membrane receptor, cytosolic bile acid binding proteins, and basolateral anion exchange proteins. The enterohepatic recirculation of BSs is approximately 98% efficient (23).


Digestion and Absorption of Phospholipids

Dietary PLs comprise only a small portion of ingested lipid; however, PLs are secreted in large quantities in bile. PLs assist in emulsification of TG droplets, as well as in micellar solubilization of CH. In particular, phosphatidylcholine (PC) is also essential in the stabilization of the micelle within the unstirred water layer. PLs of both dietary and biliary origins are digested through cleavage by phospholipase A2, a pancreatic enzyme secreted in bile. In contrast to pancreatic lipase, phospholipase A2 cleaves FAs at the sn-2 position of PLs, thus yielding lysophosphoglycerides and free FAs. These products undergo absorption through a similar process, as described earlier.


Digestion and Absorption of Sterols

CH within the intestine originates from both diet and bile. The amount of CH in the diet varies markedly depending on the degree of inclusion of foods from nonplant sources, whereas biliary CH secretion is more consistent. Dietary CH and biliary CH differ in several ways. Biliary CH is also absorbed at a site more proximal than diet-derived CH within the small intestine.

Being hydrophobic, CH requires a specialized system for digestion and absorption to occur within a watersoluble environment. Notably, absorption efficiency for CH is much less than for TG, and the major rate-limiting factor is the poor micellar solubility of CH. Using various methodologies, investigators have demonstrated that only 40% to 65% of CH is absorbed over the physiologic range of CH intakes in humans (24). The digestion of dietary CE involves release of the esterified FAs through the action of a BS-dependent CE hydrolase secreted by the pancreas. Removal of esterified FAs does not appear to be rate limiting, because mixtures of free and esterified CH are absorbed with equal efficiency in rats (25). Free sterol then undergoes solubilization within mixed micelles in the upper small intestine. It is now recognized that the uptake of dietary and endogenous CH into intestinal enterocytes is tightly controlled by apical membrane-bound proteins that serve as gatekeepers of intestinal CH absorption. Niemann-Pick-C1-like 1 (NPC1L1) was characterized in an attempt to identify proteins involved in intracellular CH trafficking (26). Shortly thereafter, NPC1L1 was singled out as the putative intestinal CH transporter using a genomics-bioinformatics approach that identified possible transporter candidates based on anticipated structural characteristics including a transmembrane sequence and a sterol sensing domain (27).

Alternatively, adenosine triphosphate (ATP)-binding cassette transporters ABCG5 and ABCG8 exist as CH efflux proteins on the apical surface of the intestinal enterocyte. Mutations in intestinal ABCG5 and ABCG8 cause sitosterolemia, a rare inherited disease characterized by the hyperabsorption of plant sterols and premature atherosclerosis (28). Studies have greatly advanced our knowledge of the structure and function of these genes and have demonstrated that ABCG5 and ABCG8 have the following characteristics: (a) each contains 13 exons organized in head-to-head conformation and separated by a small (<160 bases) intergenic region; (b) these are halftransporters that must heterodimerize in the endoplasmic reticulum (ER) to become a functional export pump; (c) they are expressed on the apical surface of intestinal enterocytes and the canalicular membrane of hepatocytes; and (d) they function in the efflux of neutral sterols from the enterocyte into the intestinal lumen and to promote biliary secretion of neutral sterols from the liver (27).

The amount of CH in circulatory lipoproteins appears to be marginally responsive to the amount of dietary CH within the normal, physiologic range. Likely, compensatory
changes in CH absorption and biosynthesis serve to protect circulatory CH levels from shifting greatly in response to changes in dietary intake (29). In contrast to CH, plant sterol absorption is very limited and differs across dietary phytosterols. For the major plant sterol β-sitosterol, typical absorption efficiency is 4% to 5%, approximately one tenth that of CH. Absorption efficiency is higher for campesterol; approximately 10%, and almost nonexistent for sitostanol (30, 31). This structure-specific discrimination depends on both the number of carbon atoms at the C24 side-chain position and the degree of hydrogenation of the sterol nucleus. Differences in absorption across phytosterols are reflected in their circulating concentrations. Plasma campesterol levels are usually higher than those of sitosterol, whereas highly saturated sitostanol is almost undetectable (14).








TABLE 4.3 PHYSICAL-CHEMICAL CHARACTERISTICS OF THE MAJOR LIPOPROTEIN CLASSES



























































LIPOPROTEIN


DENSITY (g/dL)


MOLECULAR MASS (DALTONS)


DIAMETER (nm)


LIPID (%)a


TRIGLYCERIDE


CHOLESTEROL


PHOSPHOLIPID


Chylomicrons


0.95


1400 × 106


75-1200


80-95


2-7


3-9


VLDL


0.95-1.006


10-80 × 106


30-80


55-80


5-15


10-20


IDL


1.006-1.019


5-10 × 106


25-35


20-50


20-40


15-25


LDL


1.019-1.063


2.3 × 106


18-25


5-15


40-50


20-25


HDL


1.063-1.21


1.7-3.6 × 105


5-12


5-10


15-25


20-30


HDL, high-density lipoprotein; IDL, intermediate-density lipoprotein; LDL, low-density lipoprotein; VLDL, very-low-density lipoprotein.


a Percentage composition of lipids; apolipoproteins make up the rest.


Reprinted with permission from WB Saunders from Ginsberg HN. Lipoprotein metabolism and its relationship to atherosclerosis. Med Clin North Am 1994;78:1-20.


Reasons for the low absorption efficiency of phytosterols are twofold. First, apical ABCG5 and ABCG8 transporters possess high affinity for phytosterols and preferentially excrete them back into the intestinal lumen. Second, inadequate esterification of phytosterols may occur within enterocyte membranes. Acyl coenzyme A (CoA):CH acyltransferase (ACAT)-dependent esterification of CH exceeds that of β-sitosterol (32).

Dietary phytosterols appear to compete with each other and with CH for absorption. Sitosterol consumption results in reduced absorption of CH, and that, in turn, lowers circulating CH levels. Addition of sitostanol to diets causes a depression in circulating levels of both CH and unsaturated plant sterols (11) apparently through a reduction in intestinal absorption of both types of sterols. Saturated and unsaturated plant sterols and their esters are useful in lowering serum total lipoprotein and lowdensity lipoprotein (LDL) CH levels (32).


TRANSPORT AND METABOLISM


Solubility of Lipids

Transport of largely hydrophobic lipids through the circulation is achieved in large part using aggregates of lipids and protein called lipoproteins. Principal lipid components of lipoproteins are TGs, CH, CE, and PLs. Protein constituents termed apolipoproteins, or apoproteins, serve to increase both particle solubility and recognition by enzymes and receptors located at the outer surface of lipoproteins. The major lipoprotein classes are listed in Table 4.3. Lipoproteins differ in composition; however, all types feature hydrophilic apolipoproteins, PL polar headgroups, and CH hydroxyl groups facing outward at the water interface, with PL acyl tails and CH steroid nuclei oriented toward the interior of the lipoprotein particle. Hydrophobic CE and TG molecules form the core of the lipoprotein particle. In this manner, hydrophobic lipids can be internally solubilized and transported within the aqueous media of lymph, plasma, and extracellular fluids. Although lipoproteins discussed here and in later chapters are characterized into subclasses, they represent a continuous spectrum of lipoprotein particles varying in size, density, composition, and function. Internal transport of lipids can be divided into exogenous and endogenous systems that reflect lipids of dietary and internal origins, respectively.


Exogenous Transport System

The exogenous transport system transfers lipids of intestinal origin to peripheral and hepatic tissues (Fig. 4.3). The exogenous system commences with reorganization in the enterocyte of absorbed FAs, 2-MGs, lysophospholipids, PLs, smaller amounts of glycerol, and CH into chylomicrons. Chylomicron TGs are reassembled predominantly using the monoacylglycerol pathway. Absorbed FAs are activated by microsomal FA-CoA synthase to yield acyl- CoA and are then combined sequentially with 2-MGs through the action of MG and DG acyltransferases.

Chylomicron assembly within the intestinal enterocyte is tightly regulated by the production of apolipoprotein-B (Apo-B) and the activity of microsomal TG transfer protein (MTP), which transfers lipids onto nascent Apo-B particles (33). Furthermore, the synthesis of new lipid appears to be a driving force in assembly and secretion of lipoproteins. Uptake of dietary LCFAs, incorporation into TGs by the glycerol-3-phosphate pathway, and assembly of lipoproteins all require FABP (34).







Fig. 4.3. Exogenous and endogenous pathways of lipid transport.

Not all FAs must be incorporated into chylomicrons for transport. FAs less than 14 carbons in length and those containing several double bonds undergo, to a variable degree, direct internal transport via the portal circulation that may be either as lipoprotein-bound TGs or as albumin-bound free (unesterified) FAs. Portal transfer results in more immediate delivery of FAs to the liver compared with chylomicron transit. Chylomicrons released from mucosal cells circulate first through the intestinal lymphatic system and the thoracic duct and then enter the superior vena cava. Release into the circulation is followed by TG hydrolysis at the capillary surface of tissues by lipoprotein lipase (LPL). Hydrolysis of TGs within the core of the chylomicron results in movement of FAs into tissues and subsequent production of TG-depleted chylomicron remnant particles. Chylomicron remnants then pick up CE from high-density lipoproteins (HDLs) and are rapidly taken up by liver.


Endogenous Transport System

The endogenous shuttle for lipids and their metabolites consists of three interrelated components. The first, involving very-low-density lipoproteins (VLDLs), intermediate- density lipoproteins (IDLs), and LDLs, coordinates movement of lipids from liver to peripheral tissues. The second, involving HDLs, encompasses a series of events that returns CH from peripheral tissues to liver, termed reverse CH transport. The third component of the system, not involving lipoproteins, affects the free FA-mediated transfer of lipids from storage reservoirs to metabolizing organs.

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Jul 27, 2016 | Posted by in PUBLIC HEALTH AND EPIDEMIOLOGY | Comments Off on Lipids, Sterols, and Their Metabolites1
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