BIOCHEMISTRY: A TEXTBOOK FOR HIGHER EDUCATION - E. S. Severin - 2004

CHAPTER 8. LIPID METABOLISM

II. Digestion and Absorption of Dietary Lipids

The Human Body ingests between 80 and 150 g of Lipids daily. Fats constitute the bulk of these lipids, serving as major Energy Sources alongside glucose. Although the caloric density of fats is significantly higher than that of CARBOHYDRATES (9 kcal/g compared to 4.7 kcal/g), A balanced diet dictates that fats should provide no more than 30% of total daily calories. Liquid fats (oils) contain polyunsaturated Fatty acids that cannot be synthesized by the body; therefore, they must account for at least one-third of dietary fat intake. Lipids also supply the body with Fat-soluble Vitamins A, D, E, and K. The Digestion of dietary lipids takes place in the intestines. Following absorption, the primary products of Hydrolysis (Fatty Acids and 2-monoacylglycerols) undergo resynthesis and are subsequently packaged into chylomicrons (CMs) within the intestinal mucosal Cells.

A. Fat Emulsification

Fats comprise up to 90% of dietary lipids. Although fat digestion occurs primarily in the Small Intestine, a minor fraction of dietary fats is hydrolyzed in The Stomach by "lingual lipase." This enzyme is synthesized by glands on the dorsal surface of the Tongue and is relatively resistant to the acidic pH of gastric juice. Consequently, it acts on dietary fats in the stomach for 1–2 hours. However, THE CONTRIBUTION OF this lipase to overall fat digestion in adults is negligible, with the primary digestive process taking place in the small intestine.

Because fats are Water-insoluble compounds, they can only be acted upon by water-soluble Enzymes at the water-lipid phase boundary. Therefore, the action of pancreatic lipase, which hydrolyzes fats, must be preceded by lipid emulsification. Emulsification (the mixing of fat with water) occurs in the small intestine through the action of Bile salts (Fig. 8-11). Bile acids are synthesized from Cholesterol in The Liver and secreted into the Gallbladder. The Contents of the gallbladder constitute bile, a viscous, yellowish-green fluid consisting primarily of bile acids, along with minor amounts of Phospholipids and cholesterol. Bile acids are predominantly conjugated bile acids, such as taurocholic and glycocholic acids (see Fig. 8-10 above). Following the ingestion of a fatty meal, the gallbladder contracts, releasing bile into the lumen of the duodenum. Bile acids act as detergents, orienting themselves On the surface of fat droplets to lower surface tension. As a result, large fat droplets break down into numerous smaller ones, achieving fat emulsification. This emulsification vastly increases the surface area of the lipid-water interface, thereby accelerating fat hydrolysis by pancreatic lipase. Intestinal peristalsis further facilitates this emulsification process.

Class="center">Fig. 8-11. Stages of exogenous fat assimilation in the body.

B. Hormones Stimulating Fat Digestion

When food enters the stomach and subsequently the small intestine, mucosal Cells of the small intestine begin secreting the peptide hormone cholecystokinin (pancreozymin) into the bloodstream. This hormone acts on the gallbladder to stimulate its contraction and on the exocrine cells of the Pancreas to stimulate the secretion of digestive enzymes, including pancreatic lipase. In response to the influx of acidic chyme from the stomach, other cells in the small intestinal mucosa release the hormone secretin. Secretin is a peptide hormone that stimulates the secretion of bicarbonate (HCO₃) into pancreatic juice.

C. Digestion of Fats by Pancreatic Lipase

Fat digestion essentially involves the hydrolysis of fats by pancreatic lipase. The optimal pH of ~8 for pancreatic lipase is achieved by neutralizing the acidic stomach contents with bicarbonate secreted as part of the pancreatic juice:

Н⁺ + НСO₃^- —> H₂CO₃ —> H₂O + CO₂ ↑.

The released carbon dioxide further AIDS in mixing the contents of the small intestine.

Pancreatic lipase is secreted into the lumen of the small intestine from the pancreas alongside a protein called colipase. Colipase enters the intestinal lumen in an inactive form and is converted into its active form via partial proteolysis by Trypsin. Through its hydrophobic domain, colipase binds to The surface of emulsified fat micelles. Another region of the molecule facilitates a conformational change in pancreatic lipase, bringing the enzyme's Active Site into close proximity with its substrates—fat molecules (Fig. 8-12)—thereby dramatically increasing The rate of fat hydrolysis.

Fig. 8-12. Arrangement of pancreatic lipase and colipase at the water-lipid phase boundary.

Pancreatic lipase hydrolyzes fats preferentially at the 1- and 3-positions (Fig. 8-13); consequently, the primary products of hydrolysis are free fatty acids and 2-monoacylglycerols (β-monoacylglycerols).

Fig. 8-13. Hydrolysis of triacylglycerols by pancreatic lipase.

2-Monoacylglycerol molecules also possess detergent properties, thereby contributing to further fat emulsification.

D. Digestion of Other Lipids

In addition to fats, the diet contains phospholipids and cholesterol esters, although the quantities of these lipids are considerably lower than those of fats (~40%).

Digestion of Glycerophospholipids

Several pancreatic enzymes are involved in the digestion of glycerophospholipids. Phospholipase A₂ hydrolyzes the ester bond at the second carbon atom of glycerol, converting glycerophospholipids into the corresponding lysophospholipids. Figure 8-14 illustrates an example of phosphatidylcholine hydrolysis during digestion.

Fig. 8-14. Digestion of phosphatidylcholines.

Phospholipase A₂ is secreted into the intestine as a zymogen and is activated within the intestinal lumen via partial proteolysis. Calcium Ions are required for phospholipase A₂ activity.

The fatty acid at position 1 is cleaved by lysophospholipase, and glycerophosphocholine is further hydrolyzed into glycerol, Choline, and phosphoric acid, which are then absorbed. Lysophospholipids are efficient fat emulsifiers that accelerate its digestion.

Digestion of Cholesterol Esters

In food, cholesterol is present mainly in the form of esters. The hydrolysis of cholesterol esters is catalyzed by cholesterol esterase, an enzyme also synthesized in the pancreas and secreted into the intestine (Fig. 8-15). The hydrolysis products (cholesterol and fatty acids) are absorbed as components of mixed micelles.

Fig. 8-15. Hydrolysis of cholesterol esters in the small intestine.

D. Fat Digestion in Infants

For infants and young children, milk is the primary food. Milk contains fats composed mainly of fatty acids with short and medium aliphatic chains (4-12 carbon atoms). Milk fats are already in an emulsified, water-mixed state, making them immediately accessible for Enzymatic hydrolysis. In the stomach of infants, milk fats are acted upon by lingual lipase, which is synthesized by lingual glands. In addition, the stomach of infants and young children produces gastric lipase, which is active at the neutral pH characteristic of infant gastric juice and inactive in adults (where gastric juice pH is ~1.5). This lipase hydrolyzes fats by cleaving fatty acids primarily at the third carbon atom of glycerol. Subsequently, milk fat hydrolysis continues in the intestine through the action of pancreatic lipase. Short-chain fatty acids, being water-soluble, are partially absorbed directly in the stomach. The remaining Fatty acids are absorbed in the small intestine. Fats serve as the primary energy source for infants, whereas in properly nourished adults, glucose is the main energy source. Consequently, impaired fat DIGESTION AND ABSORPTION is more dangerous in infants than in adults.

E. Absorption of Lipid Hydrolysis Products in the Small Intestine. Fat Resynthesis

Formation of Mixed Micelles and Absorption of Hydrolysis Products

The products of lipid hydrolysis—long-chain fatty acids, 2-monoacylglycerols, cholesterol, and bile acid salts—form structures called mixed micelles in the intestinal lumen. Mixed micelles are organized such that the hydrophobic PARTS OF THE molecules face inward, while the hydrophilic parts face outward, allowing the micelles to dissolve readily in the aqueous phase of the small intestinal contents. Micelle stability is maintained primarily by bile acid salts. Micelles approach the brush border of the small intestinal mucosal cells, and their lipid components diffuse across the membranes into the cells. Fat-soluble vitamins A, D, E, K, and bile acid salts are absorbed along with the lipid hydrolysis products. Bile acid salts are most actively absorbed in the ileum. Bile acids then travel via the portal vein to the liver, are re-secreted into the gallbladder, and participate once again in fat emulsification. This pathway of bile acids is termed the enterohepatic Circulation. Each bile acid molecule undergoes 5 to 8 cycles per day, and about 5% of bile acids are excreted in the feces.

The absorption of medium-chain fatty acids, generated for instance during the digestion of milk lipids, occurs without the participation of mixed micelles. These fatty acids pass from the small intestinal mucosal cells into the Blood, bind to the protein albumin, and are transported to the liver.

Fat Resynthesis in the Mucosa of the Small Intestine

Following the absorption of lipid hydrolysis products, fatty acids and 2-monoacylglycerols within the mucosal cells of the small intestine undergo resynthesis to form triacylglycerols (Fig. 8-16). Fatty acids enter the Esterification reaction only in their active form as coenzyme A derivatives; therefore, The First stage of fat resynthesis is the fatty acid activation reaction: HS CoA + RCOOH + ATP —> R-CO ~ CoA + AMP + H₄P₂O₇.

Fig. 8-16. Resynthesis of fats in the cells of the small intestinal mucosa.

The reaction is catalyzed by the enzyme acyl-CoA synthetase (thiokinase). Subsequently, acyl~CoA participates in the esterification of 2-monoacylglycerol, forming first diacylglycerol and then triacylglycerol. Fat resynthesis reactions are catalyzed by Acyltransferases.

As a rule, only long-chain fatty acids participate in fat resynthesis reactions. Fat resynthesis involves not only fatty acids absorbed from the intestine but also those synthesized within the body; consequently, the composition of resynthesized fats differs from that of dietary fats. However, the capacity to "adapt" the composition of dietary fats to human body fat during resynthesis is limited. Therefore, when dietary fats containing unusual fatty acids (such as mutton fat) are consumed, adipocytes accumulate fats containing acids characteristic of mutton fat (saturated Branched-Chain Fatty Acids). The intestinal mucosal cells actively synthesize glycerophospholipids, which are essential for forming the Structure of Lipoproteins—the transport forms of lipids in the blood.

Formation of Cholesterol Esters

In the mucosal cells of the small intestine, absorbed cholesterol molecules are also converted into esters through interaction with acyl-CoA (Fig. 8-17). This reaction is catalyzed by acyl-CoA:cholesterol acyltransferase (ACAT). The rate of exogenous cholesterol entry into the body depends on The activity of this enzyme.

In the epithelial cells of the small intestine, lipoprotein complexes known as chylomicrons (CM) are assembled from newly resynthesized fats, cholesterol esters, and dietary fat-soluble vitamins. The chylomicrons then deliver lipids to peripheral Tissues.

Fig. 8-17. Cholesterol esterification reaction in the mucosal cells of the small intestine. ACAT — acyl-CoA:cholesterol acyltransferase.

Impaired Fat Digestion and absorption. Steatorrhea

Fat maldigestion can result from several causes. One of them is impaired bile secretion from the gallbladder due to a mechanical obstruction of bile outflow. This condition may stem from the narrowing of the bile duct lumen by gallstones, or from compression of the bile duct by a tumor developing in the surrounding tissues. Reduced bile secretion leads to impaired emulsification of dietary fats and, consequently, a decreased ability of pancreatic lipase to hydrolyze fats.

Impaired secretion of Pancreatic juice and, consequently, insufficient secretion of pancreatic lipase also lead to a reduced rate of fat hydrolysis. In both cases, impaired fat digestion and absorption result in an increased amount of fat in the feces, causing steatorrhea (fatty stools). Under normal conditions, the fat content in feces does not exceed 5%. Steatorrhea impairs the absorption of fat-soluble vitamins (A, D, E, K) and Essential Fatty Acids; therefore, prolonged steatorrhea leads to a deficiency of these essential nutritional factors accompanied by corresponding clinical symptoms (see Section 3). When fat digestion is impaired, non-lipid substances are also poorly digested because fat envelops food particles and prevents enzymes from acting upon them.