Digestion in Mouth and Esophagus
Digestion of dietary lipids and their metabolites evokes a series of specific processes that enable absorption through the water-soluble environment of the gut ( Table. 4.2). Digestion begins in the oral cavity with salivation and mastication. Lingual lipase, released from the serous glands of the tongue with saliva, starts the hydrolysis of free FA from TG. Mechanical dispersion by chewing enlarges the surface area upon which lingual lipase can act. Lingual lipase cleaves at the sn-3 position, preferentially hydrolyzing shorter-chain FA found in foods, such as milk. Hydrolysis continues in the stomach, where gastric lipase promotes further lipid digestion, preferring TG containing SCFA. Fat entering the upper duodenum is 70% TG, with the remainder being a mixture of partially digested hydrolysis products.
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Table 4.2 Factors Involved in the Digestion of Fats
Intestinal digestion requires bile salts (BS) and pancreatic lipase. BS, PL, and sterols are the three principal lipid components of bile, the emulsifying fluid produced by the liver. BS consist of a steroid nucleus and an aliphatic side chain conjugated in an amide bond with taurine or glycine. The number and orientation of hydroxyl groups on the nucleus vary. The hydroxyl and ionized sulfonate or carboxylate groups of the conjugate make BS water soluble. Primary BS, defined as those synthesized directly from hepatic CH, include the tri- and dihydroxy bile salts, cholate and chenodeoxycholate, respectively. Secondary BS, including deoxycholate and lithocholate, are produced from primary BS via bacterial action on cholate and chenodeoxycholate in the gut, respectively. Further modification of secondary BS by hepatocytes or bacteria produces sulfate esters of lithocholate and ursodeoxycholate. Biliary phosphatidylcholine (PC), the main PL in bile, typically contains palmitic acid (C16:0) in the sn-1 position and an unsaturated 18- or 20-carbon FA in the sn-2 position.
Pancreatic lipase, the principal enzyme of TG digestion, hydrolyzes ester bonds at the sn-1 and sn-3 positions of the glycerol moiety ( Fig.AS). BS 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 of pancreatic lipase by binding lipase, ensuring its adhesion to the droplet. Then, through its affinity to BS, PL, and CH, colipase facilitates shuttling of hydrolysis product monoglycerides (MG) and free FA from the lipid droplet into the BS-containing micelle. FA linked at the sn-2 position of MG, PL, and cholesterol esters (CE) are resistant to hydrolysis by lipase. Lipolysis by pancreatic lipase is extremely rapid, so MG and free FA production is faster than their subsequent incorporation into micelles (12). Synthesis of both lipase and colipase is stimulated by the hormone secretin and the presence of dietary TG in the small intestine. Release of BS and pancreatic lipase is also regulated humorally. The presence of amino acids and fat digestion products in the digesta evokes release of cholecystokinin (CCK) and secretin into the circulation. CCK then stimulates the production of exocrine pancreatic enzymes, while secretin enhances output of pancreatic electrolytes. CCK also induces synthesis of hepatic bile and its release through contraction of the gall bladder.
Figure 4.3. Transport hypothesis of fatty acids and 2-monoglycerides through lipase-mediated hydrolysis, micellar transfer, and cellular uptake stages.
In breast-fed infants, TG are digested by the concerted action of gastric lipase, colipase-dependent pancreatic lipase, and a bile salt-stimulated lipase (BSSL) present in breast milk. Gastric lipase initiates digestion of the milk fat globule, and BSSL nonselectively converts the resulting MG and free FA to glycerol and free FA. This process increases absorptive efficiency.
Micellar solubilization of fat hydrolysis products occurs through the amphipathic actions of BS and PL, which are secreted at a ratio of approximately 1:3. CH is present in bile only in the unesterified form, which is the major sterol form (13). The polar termini of BS orient toward the aqueous milieu of the chyme, while the nonpolar termini containing hydrocarbon groups face the center of the micelle. BS and PL naturally aggregate so that nonpolar termini form a hydrophobic core. For micelles to form, a threshold concentration of BS must be reached, termed the critical micellar concentration (CMC). The typical biliary CMC of BS is 2 mM. BS concentrations within the proximal duodenum generally remain well in excess of this threshold.
Incorporation of MG hydrolyzed from TG into micelles increases the ability of the particle to solubilize free FA and CH. BS micelles generally possess the highest affinity for MG and unsaturated long-chain free fatty acids (LCFA) (14). Both diglycerides (DG) and TG have limited incorporation into micelles. Upon formation, mixed micelles containing FA, MG, CH, PL, and BS migrate to the unstirred water layer adjacent to the brush border surface.
Fat digestion has been the focus of clinical attention in light of the increasing global prevalence of obesity. Creation of fat substitutes that have properties similar to those of a naturally occurring fat, but which are resistant to the action of pancreatic lipase, has been actively pursued. Olestra, formed by chemical combination of sucrose with FA, possesses "mouthfeel" and texture similar to those of TG. However, Olestra passes through the intestine undigested and unabsorbed ( 15). The product is heat stable and has been approved for use in certain foods. The efficacy of Olestra in long-term weight control remains to be confirmed ( 16). Consumption of Olestra is not without risk of side effects, including anal leakage and reduced absorption of fat-soluble vitamins.
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 high intermicellar contact. This contact results in partitioning of constituents from more- to less-populated micelles, which equalizes the overall micellar concentration of digestion products. Thus, during digestion of a bolus of fat, micelles pick up evenly and rapidly the 2-MG and free FA that are released by the action of pancreatic lipase until the micelles are saturated with them.
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 for two reasons. First, micelles are much smaller (30 to 100 A) than emulsified droplets of fat (25,000 ± 20,000 A). Second, the hydrophobic nature of the larger lipid droplet results in reduced solubilization at the site of the unstirred water layer.
Transport of micellar products across the unstirred water layer into the enterocyte is described in Figure...4.3. Micelles closest to the plasma membrane of the brush border partition their digestion products across the water envelope in a concentration-dependent fashion. Digestion products continue to be shuttled between micelles across the unstirred water layer, creating a chain-reaction effect. This action hinges on the lower cellular concentration of digestion products at the enterocyte. Intestinal fatty acid-binding proteins (FABP) assist in transmucosal shunting of digestion product FA and possibly MG and BS. Elevated FABP activity in the distal bowel is associated with higher FA absorption (17).
The overall efficiency of fat absorption in human adults is about 95%, more or less independent of the amount of fat consumed. However, the qualitative nature of the dietary fat influences overall efficiency. In general, efficiency increases with the degree of FA unsaturation ( 18). There is also evidence that as FA chain length increases, absorption efficiency decreases. Likewise, the positional distribution of Fa on dietary TG is an important determinant of the eventual efficiency of absorption. Studies with structured lipids have shown that when octanoate, palmitate, or linoleate was substituted at different sn positions on a TG molecule, the positional distribution altered digestion, absorption, and lymphatic transport of these two FA ( 19, 20). The natural tendency of C16:0 to locate at the sn-2 position in breast milk may therefore explain the high digestibility of this milk fat. FA with chain lengths less than 12 carbon atoms are also absorbed passively by the gastric mucosa and taken up by the portal vein (21).
Micellar BS are not absorbed with fat digestion products but are reabsorbed further along the gastrointestinal tract. Passive intestinal absorption of unconjugated BS 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 BS is approximately 97 to 98% efficient ( 22). Although bile acid production and secretion is normally not rate limiting in lipid absorption, it has been proposed that bile acid synthesis may be subnormal in infants. Dietary taurine supplementation results in higher bile acid excretion and FA absorption in preterm and small-for-gestational-age infants ( 23).
Dietary PL constitute only a small portion of ingested lipid; however, PL are secreted in large quantities in bile. PL assist in emulsification of TG droplets as well as micellar solubilization of CH and other lipid-soluble components of the diet. PL, in particular PC, are also essential for stabilization of the micelle within the unstirred water layer. PL of both dietary and biliary origin are digested through cleavage by phospholipase A 2, a pancreatic enzyme secreted in bile. In contrast to pancreatic lipase, phospholipase A2 cleaves FA at the sn-2 position of PL, yielding lysophosphoglycerides and free FA. These products undergo absorption through a process similar to that described above.
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; biliary CH secretion is more consistent. Dietary and biliary CH differ in several ways. Dietary CH is up to 65% esterified, while biliary CH exists in free form, which probably explains the different absorption efficiencies of dietary (34%) and biliary (46%) CH ( 24). Biliary CH is also absorbed at a site more proximal within the small intestine.
CH, being hydrophobic, requires a specialized system so that digestion and absorption can occur within a water-soluble environment. The absorption efficiency for CH is much lower than that of TG. The major rate-limiting factor associated with the lower absorption of CH is its poor micellar solubility. Using various techniques, it has been demonstrated that 40 to 65% of CH is absorbed over the physiologic range of CH intakes in humans ( 23).
Digestion of dietary CE involves release of the esterified FA by a BS-dependent CE hydrolase secreted by the pancreas. Removal of esterified FA does not appear to be rate limiting; mixtures of free and esterified CH were absorbed with equal efficiency in rats ( 25). Free sterol then is solubilized within mixed micelles in the upper small intestine. Water-soluble lipid-exchange proteins of low molecular weight, located on the luminal side of the brush border membrane, may be involved in the transmembrane movement of CH and PL (26). The concentration of sphingomyelin within the apical membrane of the intestinal cell may also regulate the rate of CH uptake from micelles.
The amount of CH in the circulatory lipoproteins appears to be marginally responsive to the amount of dietary CH, within the normal physiologic range. Likely, compensatory changes in CH absorption (27) and biosynthesis (28) serve to maintain circulatory CH levels in the face of changes in dietary intake.
In contrast to CH, plant sterol absorption is very limited and differs across dietary phytosterols. For the major plant sterol, b-sitosterol, the typical absorption efficiency is 4 to 5%, about 1/10th that of CH (29). Absorption efficiency is higher for campesterol, about 10% (29), and almost nonexistent for sitostanol (30). This structure-specific discrimination depends on both the number of carbon atoms at the C24 position of the sterol side chain and the degree of hydrogenation of the sterol nucleus double bond. Differences in absorption across phytosterols are reflected in their circulating concentrations. Plasma campesterol levels are usually higher than those of sitosterol, while circulating levels of highly saturated sitostanol are almost nonquantifiable ( 11).
Phytosterol absorption is markedly reduced for two reasons. First, solubilization of phytosterols within micelles may be considerably lower than that of CH. Second, inadequate esterification of phytosterols may occur within the enterocyte membranes. Acylcoenzyme A:cholesterol acyltransferase (ACAT)-dependent esterification of CH is at least 60 times that of b-sitosterol (31).
Dietary phytosterols appear to compete with each other and with CH for absorption. Sitosterol consumption reduces absorption of CH, which in turn lowers circulating CH levels. Moreover, addition of sitostanol to diets lowers circulating levels of CH more than addition of nonsaturated plant sterols does ( 11), apparently through more effective reduction in absorption of CH and unsaturated FA (30). Saturated plant sterol esters, such as sitostanol esters, may be useful in lowering total and low-density-lipoprotein (LDL) CH levels in serum (32).
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