Pancreas, bile salts

The intestinal absorption of dietary cholesterol esters occurs only after hydrolysis by sterol esterase steryl-ester acylhydrolase (cholesterol esterase, EC 3.1.1.13) in the presence of taurocholate [113][114], This enzyme is synthesized and secreted by the pancreas. The free cholesterol so produced then diffuses through the lumen to the plasma membrane of the intestinal epithelial cells, where it is re-esterified. The resulting cholesterol esters are then transported into the intestinal lymph [115]. The mechanism of cholesterol reesterification remained unclear until it was shown that cholesterol esterase EC 3.1.1.13 has both bile-salt-independent and bile-salt-dependent cholesterol ester synthetic activities, and that it may catalyze the net synthesis of cholesterol esters under physiological conditions [116-118], It seems that cholesterol esterase can switch between hydrolytic and synthetic activities, controlled by the bile salt and/or proton concentration in the enzyme s microenvironment. Cholesterol esterase is also found in other tissues, e.g., in the liver and testis [119][120], The enzyme is able to catalyze the hydrolysis of acylglycerols and phospholipids at the micellar interface, but also to act as a cholesterol transfer protein in phospholipid vesicles independently of esterase activity [121],... 

These agents are administered to aid in the digestion of food. The primary digestant preparations contain pancreatic enzymes or bile salts. Pancreatic enzymes such as amylase, trypsin, and lipase are responsible for digestion of carbohydrates, proteins, and lipids, respectively. These enzymes are normally synthesized in the pancreas and secreted into the duodenum via the pancreatic duct. Bile salts are synthesized in the liver, stored in the gallbladder, and released into the duodenum via the common bile duct. Bile salts serve to emulsify lipids in the intestinal tract and are important in lipid digestion and absorption. 

Enzymes can be liberated from enteric-coated formulations by the neutral to slightly alkaline pH caused by secretions front die pancreas, the gall bladder, and the intestinal mucosa. They have a hydrogen carbonate concentration of about SS mM, which causes an increase in pH. Bile salts decrease the interfadal tension, promoting the liberation of drugs from solid dosage forms. 

Pancreatic carboxytester lipase, secreted by the pancreas as an active enzyme without proteolytic activation, displays broad substrate specificity and has therefore received many names in the literature carboxylesteraae, bile salt-stimulated (or activated or dependent) lipaae (due to its absolute requirement for bile salts to hydrolyze insoluble substrates), carbaxylester lipase or hydrolase, cholesterol... 

Absorption of fat in the newborn, and particularly in premature infants, is much less efficient than in adults due to the relatively low output of lipase and bile salts from the pancreas of the infant. Intragastric lipolysis by milk BSSL and lingual or salivary lipases, the secretion of which is stimulated by suckling, appears to augment the pancreatic lipase system in the newborn (Hamosh, 1979 Hernell and Blackberg, 1994). 

People of western culture ingest about 100 g of triacylglycerol per day. The digestion and absorption of this lipid, together with the ingested phospholipids, depend on secretions from the pancreas (exocrine) and a flow of bile from the gall-bladder. The important constituents of the pancreatic secretions are enzymes, and those of the bile are the bile salts (Chap. 6). 

FIGURE 2.38 Enterohepatic circulation of bile salts. Bile salts from the liver enter the duodenum at the ampulla of Vater, the same opening through which material from the exocrine pancreas is released. Most of the gall bladder is hidden within the lobes of the liver. After varying degrees of utilization and reutilization for lipid absorption, the bile salts reach the distal ileum, where they are reabsorbed and returned to the liver via the portal vein. The portal vein is very important because it also carries water-soluble nutrients absorbed from the diet. 

Pancreatic lipase is one of the mammalian key digestive enzymes. It completes the dietary triacylglycerol breakdown initiated by preduode-nal lipases, including lingual and gastric enzymes, (see below). The enzyme is inhibited in the intestine by bile salts, but the activity is restored in the presence of colipase (CLP), a relatively short (95 residues) heat-stable polypeptide secreted by the pancreas (Semeriva and Desnuelle, 1979 Borgstrbm and Erlanson-Albertsson, 1984). The structural details of the interaction of colipase with lipase are described in Section III,C. 

Blockage of the bile duct caused by problems such as cholesterol-containing gallstones or duodenal or pancreatic tumors can lead to an inadequate concentration of bile salts in the intestine. Digestion and absorption of dietary lipids is diminished. Certain diseases that affect the pancreas can lead to a decrease in bicarbonate and digestive enzymes in the intestinal lumen. (Bicarbonate is required to raise the intestinal pH so that bile salts and digestive enzymes can function.) If dietary fats are not adequately digested, steatorrhea may result. Malabsorption of fats can lead to caloric deficiencies and lack of fat-soluble vitamins and essential fatty acids. 

C. The pancreas produces bicarbonate (which neutralizes stomach acid) and digestive enzymes (including the lipase that degrades dietary lipids). Decreased bicarbonate will lead to a decrease of intestinal pH. Decreased digestion of dietary triacylglycerols will lead to formation of fewer bile salt micelles. Intestinal cells will have less substrate for chylomicron formation, and less fat-soluble vitamins will be absorbed. More dietary fat will be excreted in the feces. 

D. In this situation, bile salts from the pancreas could not enter the digestive tract. Therefore, recycling and excretion of bile salts, digestion of fats, and formation of chylomicrons would all decrease. As a consequence, fat in the feces (steatorrhea) would increase. 

The primary functions of the small intestine are digestion and absorption of food. The adult small intestine is approximately 6 m in length and is composed of the duodenum, ileum, and jejunum. Digestion occurs primarily in the upper small intestine and requires the action of pancreatic enzymes such as amylase, lipase, and trypsin, which are released from the pancreas into the duodenum, and bile salts from the biliary system. Absorption largely takes place in lower portions of the small intestine. 

Recent studies indicate [38,39] that human pancreas carboxylester lipase and bile salt-stimulated human milk lipase share the same peptide sequence, also displaying a high degree of similarity to acetylcholine esterase. 

Topical pancreatic lipase substrates like tributyrin and triolein emulsions are hydrolyzed by carboxylester lipase in the presence of bile salt but slowly—at a rate lower than 3% and 0.5%, respectively, of that observed with the lipase-colipase complex. On the other hand, the positional specificity is not restricted all three sn positions of triglycerides can be split by the carboxylester lipase. While long-chain phospholipids are resistant, short-chain phospholipids are readily attacked by carboxylester lipase [40]. The low substrate specificity of carboxylester lipase makes possible an essential role for this enzyme in the hydrolysis of triglycerides containing certain esterified polyunsaturated fatty acids, such as eicosapentaenoic, arachidonic, or linoleic acids [41], and which may be resistant to attack by pancreas lipase (see p. 190). 

Other recombinant versions of gastric lipases are available from yeast. Pseudomonas and filamentous fungi [369]. Sheep milk-derived human bile salt-stimulated H-pase (BSSL) - an enzyme produced in the pancreas and in human milk - was developed by PPL Therapeutics for similar indications, and it is discussed below [63]. 

This enzyme (triacylglycerol acyl-hydrolase) has a molecular mass of approximately 42 kDa (Hide, Chan, and Li 1992) and a short half-life of about 1-3 h in dogs. Pancreatic lipase is secreted in its active form, and this activity is enhanced by colipase and bile salts the enzyme hydrolyzes triglycerides to monoglycerides. Other lipases— phospholipase a, phospholipase b, and cholesterol ester hydrolase—are also secreted by the pancreas. 

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