Gastric Digestion of Triacylglycerols

Digestion of triacylglycerols in humans begins in the stomach with the action of the hydrolytic enzyme, gastric lipase, which is secreted by the gastric mucosa. This lipase is most active in an acidic environment. It preferentially hydrolyzes the fatty acid at the sn-3 position of the triacylglycerol molecule, regardless of the fatty acid esterified to this position (Aloulou and Carrière, 2008), but it can also hydrolyze fatty acids at the sn-1 position (Whitcomb and Lowe, 2007). Although the optimal pH of gastric lipase is around 4, the enzyme is still active at pH 6 to 6.5 and probably continues to hydrolyze triacylglycerol in the upper duodenum where the pH is between 6 and 7. In cases of pancreatic insufficiency, gastric lipase may compensate at least partially for the loss of the pancreatic hydrolytic lipases. Overall, the net digestion of fat in the stomach is limited (less than 10% to 25%), but it contributes to the subsequent digestion of fat in the lumen. Gastric lipase plays an important role in the digestion of fat in human milk and formula by infants, who have low levels of the major hydrolytic enzyme, pancreatic lipase, until weaning (Lindquist and Hernell, 2010; Whitcomb and Lowe, 2007). As discussed later, pancreatic lipase-related protein 2 and carboxylester lipase also contribute to the digestion of fat by the infant.

The 1,2-diacylglycerols and fatty acids produced as a result of the action of gastric lipase may promote some emulsification of dietary fat in the stomach. In addition, grinding and mixing of the gastric contents contribute to dispersion into fine lipid droplets less than 0.5 mm in diameter. These droplets leave the stomach and enter the small intestine where the combined action of bile and pancreatic secretions brings about a marked change in the chemical and physical form of the dietary lipids.

Luminal Small Intestinal Digestion of Triacylglycerols

When the acidic chyme containing the lipid droplets reaches the duodenum, it triggers the secretion of cholecystokinin, which in turn triggers the release of bile from the gallbladder. Bile contains the biological detergents known as bile acids. Some of the bile acids partition onto the surface of the fine lipid droplets and contribute to their emulsification. Mixture of the chyme with the alkaline secretion of the Brunner glands and the bicarbonate-rich secretion from the pancreas occurs in the duodenum, resulting in a neutralization of the gastric acid so that the intestinal contents in humans have a slightly alkaline pH.

Pancreatic lipase, which has a pH optimum around pH 8, digests most of the triacylglycerol that enters the small intestine (Whitcomb and Lowe, 2007), acting along with the contributing activities of carboxylester lipase (Gilham et al., 2007) and possibly pancreatic lipase-related peptide 2 (Figure 10-1). Pancreatic lipase, which is secreted in its active form, works at the lipid−aqueous interface of the emulsified lipid particles and mainly hydrolyzes the sn-1 and sn-3 positions of triacylglycerol molecules to release 2-monoacylglycerol and free fatty acids. However, the bile acids at the lipid−aqueous interface of the emulsified lipid particles inhibit the action of pancreatic lipase unless colipase is present. Colipase is also secreted by the pancreas as the inactive procolipase, which is activated by trypsin-mediated proteolytic cleavage in the small intestine. The binding of colipase to the lipid–aqueous interface allows the binding and anchoring of lipase to the interface. This binding in a 1:1 molar ratio also results in important conformational changes in lipase that expose its active site and enable its hydrolytic action. Colipase deficiency in humans and mice results in fat malabsorption.

In contrast, pancreatic lipase-related protein 2 has broad activity and hydrolyzes triacylglycerols, phospholipids, and galactolipids, depending on the species (Whitcomb and Lowe, 2007) and is neither stimulated by colipase nor inhibited by bile acids. Its action appears important for triacylglycerol digestion in the newborn when its secretion is high. In knockout mice lacking pancreatic lipase-related protein 2, fat malabsorption is present in pups until weaning when pancreatic lipase secretion increases (Lindquist and Hernell, 2010).

Luminal Small Intestinal Digestion of Phospholipids

Digestion of phospholipids occurs in the small intestine through the hydrolytic action of pancreatic phospholipase A2, which acts at the lipid interface of micelles. Pancreatic phospholipase A2 acts on both the dietary and the endogenous phospholipids. The most abundant of these phospholipids is phosphatidylcholine. The pancreas secretes an inactive prophospholipase A2, which is then activated by trypsin-mediated cleavage in the lumen. Phospholipase A2 hydrolyzes the fatty acid from the sn-2 position of phosphatidylcholine to yield a fatty acid and lysophosphatidylcholine (Whitcomb and Lowe, 2007). Some minor contribution may also come from the intestinal mucosal intrinsic membrane enzyme known as retinyl ester hydrolase or phospholipase B, which has both phospholipase and retinyl ester hydrolase activities.

Luminal Small Intestinal Digestion of Cholesteryl Esters

Digestion of cholesteryl esters also occurs in the small intestinal lumen. Although most dietary and biliary cholesterol is present as the free sterol, about 10% to 15% of the total cholesterol is present as cholesteryl esters that require hydrolysis before absorption. Carboxylester lipase (also called cholesteryl ester lipase, bile acid–stimulated lipase, and nonspecific esterase) is secreted by the pancreas as an active enzyme and hydrolyzes cholesteryl ester to free cholesterol and fatty acid. Carboxylester lipase has a broad specificity and can hydrolyze triacylglycerols (at all three positions), phosphoglycerides, sphingolipids, galactolipids, vitamin A esters, and monoacylglycerols, as well as cholesteryl esters. Carboxylester lipase, like phospholipase A2, can act on substrates in bile acid micelles, and it is stimulated by bile acids, particularly trihydroxy bile acids such as cholic acid. This activation occurs through a unique conformational change resulting in the self-aggregation of carboxylester lipase in the presence of trihydroxy bile acids (taurocholate or glycocholate); this change brings about an increase in activity by protecting the enzyme from proteolytic inactivation.

Luminal Small Intestinal Digestion of Esters of Fat-Soluble Vitamins

Digestion of fat soluble vitamin esters, primarily retinyl ester, occurs in the small intestine by several enzymes including carboxylester lipase, retinyl ester hydrolase (phospholipase B),

and also pancreatic lipase (Harrison, 2005). Other fat soluble vitamins (D and E) and carotenoids are present primarily in their free unesterified forms in foods.

Relative Contributions of Lipid Digesting Enzymes

The relative contributions of lipid digesting enzymes is not fully understood but is known to depend on the stage of development and the relative availability of the various lipases. As stated earlier, gastric lipase and pancreatic lipase-related peptide 2 appear to be able to digest completely the dietary lipid in breast milk or formula, because pancreatic lipase is very low in the newborn. Carboxylester lipase is present in secreted breast milk and also contributes to fat digestion in the newborn (Whitcomb and Lowe, 2007). Studies in knockout mice lacking one or more lipases also reveal the redundancy and compensation of the lipases in lipid digestion. Deficiency of pancreatic lipase does not affect triacylglycerol absorption in mice fed a low-fat diet but reduces it in those fed a high-fat diet and also reduces cholesterol absorption (Gilham et al., 2007). Loss of carboxylester lipase does not affect retinyl ester absorption, although it does reduce cholesteryl ester absorption. Deficiency of phospholipase A2 does not affect phospholipid absorption. However, deficiency of both pancreatic lipase and carboxylester lipase reduces both triacylglycerol and retinyl palmitate digestion and absorption (Gilham et al., 2007). Similarly during pancreatic insufficiency in humans, gastric lipase contributes to the partial digestion of dietary lipid. Clearly, the overlapping and complementary functions of the lipid digesting enzymes allow for redundancy and compensation in lipid digestion.

Micellar Solubilization of Lipid Digestion Products

Micellar solubilization of the digestion products, predominantly monoacylglycerols, fatty acids, lysophosphatidylcholine, and cholesterol, is essential to their uptake by enterocytes. Micellar solubilization enables the lipid digestion products to cross the barrier presented by the unstirred water layer surrounding the epithelial surface of the small intestine. The unstirred water layer varies in thickness depending on how vigorously the intestinal contents are mixed (Figure 10-2). Without micelle formation, the low solubility of lipid digestion products in water would limit their ability to cross this unstirred layer. Micelles form when the bile acid concentration is at or above the critical micellar concentration (~1 to 2 mmol/L, depending on the specific bile acid). In the human small intestinal lumen, the bile acid concentration is almost always above the critical micellar concentration, such that bile acid micelles form (Hofmann, 2009). Once incorporated into the mixed micelles (containing bile acids and other lipid moieties), lipid digestion products readily cross the unstirred water layer, resulting in a 100- to 1,000-fold increase in the aqueous concentrations of fatty acids, monoacylglycerols, cholesterol, and lysophosphatidylcholine near the epithelial absorptive surface. Thus micellar solubilization provides an efficient mechanism for diffusion of lipid digestion products across the unstirred water layer, facilitating the subsequent uptake of these lipid molecules by the enterocytes.

The micellar phase, however, is not homogeneous. In addition to the large disc-like mixed bile acid micelles that are more or less saturated with lipids, lipid crystalline or unilamellar vesicles exist and are composed of mixed lipids saturated with bile acids (Carey et al., 1983). These vesicles may play an important role in the uptake of lipid digestion products in patients with low intraluminal bile acid concentrations (Mansbach et al., 1980) or bile fistulae (Porter et al., 1971).

Absorption of Products of Lipid Digestion by Enterocytes

Absorption of the products of lipid digestion occurs through two mechanisms: passive diffusion and carrier-mediated transport across the apical (brush border) membrane of enterocytes. Observations of saturable uptake supports the involvement of transporters in the uptake of fatty acids and cholesterol, but uptake after proteolytic treatment of the brush border membrane supports a role of passive diffusion as well.

Carrier-Mediated Uptake of Fatty Acids

Identification of specific transporters for fatty acids has been controversial. Although fatty acid transport protein 4 was initially suggested to play a role in the absorption of fatty acids, current evidence suggests that it does not (Shim et al., 2009). Instead, fatty acid transport protein 4 is localized to the endoplasmic reticulum (ER) membrane and plays a role in the intracellular processing of fatty acids (Mansbach and Gorelick, 2007). Emerging instead is the role of the fatty acid translocase, CD36 (Figure 10-3), in the absorption of fatty acids from the proximal, but not distal, intestine (Nassir et al., 2007). CD36, a glycoprotein, is a member of the type B scavenger receptor family that translocates long-chain fatty acids across the apical membrane of the enterocyte, but the precise mechanism of this transfer is not understood. CD36 may act in concert with other membrane and intracellular proteins to effect this transfer, although the nature and identity of these other proteins is not known.

Carrier-Mediated Uptake of Cholesterol

Another transport protein, NPC1L1, plays an essential role in cholesterol and phytosterol uptake (Hui et al., 2008; Betters and Yu, 2010; see Figure 10-3). The highest expression of NPC1L1 in the proximal small intestine colocalizes with the site of maximal cholesterol absorption. Both NPC1L1 and cholesterol absorption are minimal in the distal small intestine. Deficiency of NPC1L1 in knockout mice reduced cholesterol absorption by 70% (Altmann et al., 2004). Further, NPC1L1 is the target of ezetimibe, a potent inhibitor of cholesterol and plant sterol absorption (Betters and Yu, 2010). This transporter protein cycles between the apical surface and intracellular compartments of the enterocyte in a mechanism consistent with cholesterol-regulated, clathrin-mediated

NUTRITION INSIGHT

Absorption of Lipophilic Drugs and Toxins

Many lipophilic compounds, including drugs, fat-soluble vitamins, and other compounds present in food or present on food as contaminants, are incorporated into chylomicrons in the intestinal mucosal cells and transported via the lymph. Hence absorption of these compounds depends upon normal fat digestion and absorption and upon chylomicron formation and secretion. The role of dietary fat in the absorption of fat-soluble vitamins is well-known. Uptake of lipophilic drugs and toxins also may be promoted when ingested along with dietary fat. Factors that limit lipid digestion, such as blockage of biliary flow or chylomicron formation, may interfere with or prevent absorption of these compounds.

Patients are often advised to take lipophilic medications together with their meals to enhance the absorption of the drug by the gastrointestinal tract. Delivery of lipophilic drugs in forms that enhance their absorption and thus require smaller doses is of interest to pharmaceutical manufacturers. Enhancement of absorption of lipophilic compounds by the presence of dietary fat also may affect absorption of environmental contaminants or toxins. For example, absorption of DDT (1,1-bis[p-chlorophenyl]-2,2,2-trichloroethane), a toxic chlorinated hydrocarbon pesticide now banned in the United States, is enhanced by concomitant fat feeding. Enhanced absorption of lipophilic compounds by dietary fat also may account for the observation that tetrachloroethylene causes toxic effects when fed with a high-fat meal. Tetrachloroethylene is a drug used for treating hookworm infections, and it is not ordinarily absorbed from the gastrointestinal tract.

endocytosis. Details remain to be elucidated, but NPC1L1 may act as an extracellular free cholesterol receptor, recruiting extracellular cholesterol to its N-terminal until the cholesterol content in this microdomain of the apical membrane reaches the threshold necessary for endocytosis and targeting to intracellular compartments (Betters and Yu, 2010). At least two other proteins, scavenger receptor B1 (SR-B1) and CD36 may also play roles in cholesterol absorption, particularly in the proximal intestine (Hui et al., 2008). Like NPC1L1, SR-B1 is inhibited by ezetimibe. The relative contributions of NPC1L1, SR-B1, and CD36 and their potential interactions in cholesterol absorption are not fully understood.

Complicating assessment of the net absorption of cholesterol, however, is the efflux of absorbed cholesterol from the enterocyte through the ATP-binding cassette proteins (ABCG5 and ABCG8) that are located on the enterocyte’s apical membranes (Hui et al., 2008; see Figure 10-3). Their expression is highest in the proximal and midsections of the small intestine; they limit net cholesterol absorption by transporting cholesterol back into the lumen of the intestine. Furthermore, these ABC transporters efficiently transport plant sterols, which differ from cholesterol only by a methyl or ethyl group in the side chain, out of the enterocyte. Thus only a small percentage (≈1%) of ingested noncholesterol sterols are absorbed and retained in the body, whereas 50% to 60% of dietary cholesterol is absorbed and retained. This tremendous ability of the small intestine to discriminate against the plant sterols is lost in patients with β-sitosterolemia, a rare autosomal recessive disorder characterized by hyperabsorption of all sterols. Mutations in the ABCG5 or ABCG8 genes cause β-sitosterolemia (Lu et al., 2001). Many of these mutations seem to prevent formation of stable heterodimers and to impair trafficking of the sterol transporter to the apical surface of the cells (Graf et al., 2004), thus reducing the efflux of plant sterols back to the lumen of the intestine.

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