CF is a prevalent genetic disease in Caucasians of Northern European ancestry, with a prevalence of approximately 1 in every 3,300 births in the United States. It is an autosomal-recessive disorder caused by mutations in the CFTR gene, which encodes the CF transmembrane conductance regulator protein. This protein functions as a chloride channel in the pancreas, lungs, testes, and sweat glands. When the CFTR protein is defective, there is a decrease in chloride secretion and an increase in sodium and water uptake. This leads to the production of thickened mucus in the pancreas, blocking the pancreatic ducts and preventing the pancreatic enzymes from reaching the intestine. As a result, pancreatic insufficiency occurs. Treatment for CF includes enzyme replacement therapy and supplementation with fat-soluble vitamins. In addition to pancreatic insufficiency, CF also causes chronic lung infections and progressive pulmonary disease, as well as male infertility.

The process of dietary lipid emulsification, a crucial step in digestion, takes place in the duodenum. Emulsification increases the surface area of the hydrophobic lipid droplets, allowing the digestive enzymes to effectively act at the interface of the droplets and the surrounding aqueous solution. Emulsification is achieved through two mechanisms: the use of conjugated bile salts with detergent properties and mechanical mixing due to peristalsis. Conjugated bile salts, which are derived from cholesterol, interact with the dietary lipid droplets and the duodenal contents, stabilizing the droplets and preventing them from coalescing as they become smaller through peristalsis. These bile salts are synthesized in the liver, stored in the gallbladder, and released into the small intestine. It is important to note that a more detailed discussion of bile salt metabolism can be found on page 225.

The degradation (digestion) of dietary triacylglycerol (TAG), cholesteryl esters, and phospholipids in the small intestine is carried out by pancreatic enzymes, which are regulated by hormones. TAG molecules are too large to be efficiently taken up by the enterocytes (mucosal cells) of the intestinal villi. Therefore, they are hydrolyzed by pancreatic lipase, an esterase that specifically removes fatty acids from carbons 1 and 3. The primary products of this hydrolysis are 2-monoacylglycerol (2-MAG) and free fatty acids (FFA). Pancreatic lipase, present in high concentrations in pancreatic secretions, is highly efficient and ensures that significant fat malabsorption only occurs in severe cases of pancreatic deficiency, such as in CF. Colipase, another protein secreted by the pancreas, binds to lipase and anchors it at the lipid-aqueous interface in a 1:1 ratio. Colipase restores lipase activity in the presence of inhibitory substances like bile salts that bind to micelles. It is worth mentioning that colipase is initially secreted as the inactive form called procolipase, which is activated by trypsin in the intestine. Orlistat, an antiobesity drug, inhibits gastric and pancreatic lipases, thereby reducing fat absorption and resulting in weight loss.
CF is the most common lethal genetic disease in Caucasians of Northern European ancestry and has a prevalence of ~1:3,300 births in the United States. CF is an autosomal-recessive disorder caused by mutations to the gene for the CF transmembrane conductance regulator (CFTR) protein that functions as a chloride channel on epithelium in the pancreas, lungs, testes, and sweat glands. Defective CFTR results in decreased secretion of chloride and increased uptake of sodium and water. In the pancreas, the depletion of water on the cell surface results in thickened mucus that clogs the pancreatic ducts, preventing pancreatic enzymes from reaching the intestine, thereby leading to pancreatic insufficiency. Treatment includes replacement of these enzymes and supplementation with fat-soluble vitamins. [Note: CF also causes chronic lung infections with progressive pulmonary disease and male infertility.]
C. Emulsification in the small intestine
The critical process of dietary lipid emulsification occurs in the duodenum.
Emulsification increases the surface area of the hydrophobic lipid droplets so that the digestive enzymes, which work at the interface of the droplet and the surrounding aqueous solution, can act effectively. Emulsification is accomplished by two complementary mechanisms, namely, use of the detergent properties of the conjugated bile salts and mechanical mixing due to peristalsis. Bile salts, made in the liver and stored in the gallbladder, are amphipathic derivatives of cholesterol (see p. 224). Conjugated bile salts consist of a hydroxylated sterol ring structure with a side chain to which a molecule of glycine or taurine is covalently attached by an amide linkage (Fig. 15.3). These emulsifying agents interact with the dietary lipid droplets and the aqueous duodenal contents, thereby stabilizing the droplets as they become smaller from peristalsis and preventing them from coalescing. [Note: See p. 225 for a more complete discussion of bile salt metabolism.]
D. Degradation by pancreatic enzymes
The dietary TAG, cholesteryl esters, and phospholipids are enzymatically degraded (digested) in the small intestine by pancreatic enzymes, whose secretion is hormonally controlled.
1.
Triacylglycerol degradation: TAG molecules are too large to be taken up efficiently by the mucosal cells (enterocytes) of the intestinal villi. Therefore, they are hydrolyzed by an esterase, pancreatic lipase, which preferentially removes the FA at carbons 1 and 3. The primary products of hydrolysis are, thus, a mixture of 2-monoacylglycerol (2-MAG) and FFA (see Fig. 15.2). [Note: Pancreatic lipase is found in high concentrations in pancreatic secretions (2%–3% of the total protein present), and it is highly efficient catalytically, thus insuring that only severe pancreatic deficiency, such as that seen in CF, results in significant malabsorption of fat.] A second protein, colipase, also secreted by the pancreas, binds the lipase at a ratio of 1:1 and anchors it at the lipid–aqueous interface. Colipase restores activity to lipase in the presence of inhibitory substances like bile salts that bind the micelles. [Note: Colipase is secreted as the zymogen, procolipase, which is activated in the intestine by trypsin.] Orlistat, an antiobesity drug, inhibits gastric and pancreatic lipases, thereby decreasing fat absorption, resulting in weight loss.
2.