Digestion of Carbohydrates, Proteins and Fats

Abstract

The narrative above is likely an early reference to visceral fat. Digestion of food begins in our mouth with salivary amylase that acts on carbohydrates. The taste of food is only perceived by gustatory receptors on our tongue. Once swallowed, the enjoyment of any taste is over. So chew more, especially on what is called ‘fast food’!

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“Moses also took all the fat around the inner parts, the covering of the liver, both kidneys and their fat, and burned it on the altar”Leviticus

The narrative above is likely an early reference to visceral fat. Digestion of food begins in our mouth with salivary amylase that acts on carbohydrates. The taste of food is only perceived by gustatory receptors on our tongue. Once swallowed, the enjoyment of any taste is over. So chew more, especially on what is called ‘fast food’!

Metaphysiologically, it is a wonderful coincidence that digestive enzymes are secreted from our exocrine glands that hydrolyze the three major types of nutrients in our food, namely, carbohydrates, proteins, fats (and also nucleic acids, DNA, RNA).

Enzymes in saliva, gastric and pancreatic secretions act in the mouth, lumen, aided by the mixing action of the GI motility. The penultimate enzymatic actions for peptides and disaccharides to their final amino acid and monosaccharide components respectively are achieved by luminal membrane bound enzymes of the intestinal enterocytes. For small absorbable peptides, there are also intracellular peptidases that release amino acids to exit the cell by amino acid transporters at the basolateral membrane of the intestinal epithelium.

Some of the undigested food are acted upon by resident colonic bacteria, that appears to have important physio-ecological functions.

For fats, pancreatic lipase, phospholipase, cholesterol esterase act on emulsified dietary fats that are generated by bile salt actions, when bile is released by neuroendocine mechanisms, triggered by presence of fats in the duodenum.

1 Carbohydrate Digestion

Explain the following regarding the digestive breakdown of carbohydrates.

• a. Cellulose remains undigested in the diet.

• b. The only enzyme that debranches α-limit dextrin is isomaltase.

• c. Pancreatic amylase does not generate glucose from digestion.

• d. Pancreatic amylase does not completely breaks down starch to disaccharides.

• e. Disaccharidases are not secreted by the intestine.

Plant starch, amylopectin is the major source of carbohydrates in most human diet. Cellulose, the major content of dietary fiber has β 1,4 linked glucose polymer. These glycosidic linkages cannot by hydrolyzed by intestinal enzymes. The salivary and pancreatic α-amylase cannot cleave α-1,6 linkages and terminal α 1,4 bonds in the carbohydrate. The products released are maltose, maltotriose and α-limit dextrins. Isomaltase or α-dextrinase is a brush border oligosaccharidase. It breaks down the α-1,6 linkages at the branch points of the α-limit dextrins.

Pancreatic digestion of starch also produces malto oligosaccharides (4–9 glucose units) and α-limit dextrins (5–9 glucose subunits). Glucoamylase is another brush border enzyme that releases one glucose at a time from malto oligosaccharides.

Disaccharidases are also found in the mucosal epithelium of the duodenum and jejunum. Lactase cleaves lactose to glucose and galactose. Sucrase breaks down sucrose into fructose and glucose.

Sucrase and α-dextrinase are noncovalently associated as subunits of a single protein. After insertion unto the brush border membrane, pancreatic proteases hydrolyze it into the two enzyme parts.

Brush border trehalase cleaves trehalose, a 1,1 α-linked disaccharide of glucose. Trehalose is found in mushrooms and yeast.

2 Protein Digestion

Explain the statements below regarding protein digestive processes.

• a. Ingested proteins is not the only protein source for digestion.

• b. Pepsin is non-essential for protein breakdown.

• c. Small peptides are the major digestive products rather than amino acids.

• d. The digestion and absorption of all protein sources is almost complete.

• e. An intestinal enzyme converts all the trypsinogen to trypsin. Why is this statement incorrect?

Besides ingested protein, proteins are also available in the form of digestive enzymes and exfoliated epithelial cells. A small amount of protein is present only in feces. This is mainly derived from colonic bacteria, exfoliated cells and mucoproteins in colonic secretions. In human, by the end of the jejunum, ingested protein is almost all absorbed. To balance normal catabolism, the required protein/day is about 0.7 g/kg body weight.

Maximally, pepsins break down about 15 % of dietary proteins. The main products of protein digestion by pancreatic proteases and brush border peptidases are small peptides and amino acids. The former is three to four times more than the amino acids. Inside the intestinal cell, cytosolic peptidases release amino acids, especially from dipeptides and tripeptides.

The enzyme, enteropeptidase on the brush border membrane of duodenum and jejunum activates trypsinogen to trypsin. Trypsin then acts autocatalytically to convert more trypsinogen to trypsin. Trypsin also cleaves the other pancreatic proenzymes to their active forms.

The brush border peptidases include amino peptidase and dipeptidyl aminopeptidase.

3 Fat Digestion

• a. What is the principal form of phospholipids that is absorbed?

• b. What is the diameter of a mixed micelle?

• c. What products of fat digestion mainly form micelles with bile acid?

• d. How are fat-soluble vitamins absorbed?

• e. How does the micelle facilitate the brush border absorption of lipid digestion products?

Phopholipase A₂ cleaves the 2-possition ester bond of a glycophosphatides. If the substrate is phosphatidylcholine, the products will be one free fatty acid and one lysophosphatydylcholine. Prophospholipase A₂ is activated by trypsin. Both phospholipase A₂ and pancreatic lipase do not break well the fatty acyl ester linkage at the 1 position. Thus phospholipids are mainly absorbed as lysophosphatides.

Bile acids generate micelles especially with 2-monoglycerides and lysophosphatides. The hydrophobic acyl chains of 2-MG and lysophosphatides are orientated towards the interior of the micelles. Bile acids are flat amphiphatic molecules that have a polar and a non-polar domains. The non-polar face of the bile acid is directed towards the lipid interior of the micelles. Each micelle is about 5 nm in diameter and contains about 20–30 lipid molecules. The micelles are small enough to diffuse among the microvilli and facilitate the absorption of lipids. Very hydrophobic molecules like long-chain fatty acids, cholesterol and fat-soluble vitamins preferentially partition into the micellar interior. Fat-soluble vitamins, A, D, E, K are poorly absorbed if fat digestion and absorption is produced by pancreatic enzyme deficiency or obstructed bile flow.

Micelles keep the aqueous solution around them saturated with 2-MG, cholesterol, fatty acids and lysophosphatides. Because these lipids are very insoluble in water, their aqueous concentrations are low. The mixed micelles diffuse through the unstirred layer. Thus the aqueous solution in contact with the brush border is saturated with products of fat digestion, ready for absorption over the large surface area of the brush border.

4 Digestion of Lipids

• a. Does the stomach digest lipids?

• b. Are the lipolytic pancreatic enzyme water-soluble?

• c. Are bile acids good emulsifying agents?

• d. What is the diameter of an emulsion droplet?

• e. Bile salts inactivate pancreatic lipase. How does the intestinal lipid digestion proceed?

A fair amount of triglyceride digestion takes place in the stomach. The enzymes that hydrolyze lipids in the gastric phase are called pre-duodenal lipases. The enzyme activities are optimal at acid pH. Gastric lipase is produced by glands in the fundus of the stomach. If pancreatic lipase is deficient or inactivated by high acidity in the intestine, the contribution of gastric lipase to the total hydrolysis of the triglycerides becomes significant.

Pancreatic lipolytic enzymes have access only to the surface of fat droplets. Emulsification increases the total surface area for lipid digestion many thousand times. Each emulsion droplet is about 1 μm in diameter. Alone, bile acids are weak emulsifiers. In combination with the phospholipid lecithin, available in high concentration in the bile, dietary lipids are effectively emulsified. Pancreatic lipase (glycerol ester hydrolase) acts at the interface between the aqueous phase and the triglyceride oil phase. Bile salts bind to the oil droplets and prevent the lipase from acting. A cofactor in pancreatic juice, colipase is able to displace bile salts from the oil droplets. The colipase forms a complex with the pancreatic lipase. Together the enzyme complex cleaves the 1 and 1′ fatty acids from a triglyceride. This releases two free fatty acids and a 2-monoglyceride.

5 Bile

• a. Where are the two major organic constituents of bile?

• b. How many types of bile salts are present in bile?

• c. Why are bile salts more soluble than bile acids?

• d. Why does a pancreatectomized animal have steatorrhoea?

• e. Why does ileal resection lead to steatorrhoea?

Bile acids (50 %) and phospholipids (40 %) are the primary organic compounds of bile. Bilirubin (2 %) and cholesterol (4 %) are also present. The total bile acid pool is about 2.5 g (includes bile acids in the liver, gallbladder, bile ducts and intestines.

There are two primary bile acids, cholic acid and chenodeoxycholic acid. Intestinal bacteria dehydroxylate them into secondary bile acids, deoxycholic acid and lithocholic acid.

The hepatocytes conjugate bile acids with glycine or taurine. There are thus eight bile salt types, named after the parent bile acid and the conjugated amino acid (e.g taurocholic acid).

The pKs of bile acids are about 7.0. At the duodenal pH of pH 3 to 5, bile acid will be mostly nonionized and water-insoluble. Bile salts have pKs between 1 and 4. In the duodenal luminal environment, bile salts will be considerably ionized and soluble in water.

If the exocrine function of the pancreas is absent, steatorrhoea occurs because of lack of pancreatic lipase. The absence of pancreatic bicarbonate also accounts to the fatty stools. Acid not only inhibits pancreatic lipase but may also precipitate some bile salts.

In a patient after ileectomy, the fecal loss of bile acids is great and new synthesis of bile acids is stimulated. However, the hepatic production cannot keep pace with the excreted loss. The bile acid pool is reduced. Emulsification and micellar formation become inadequate. Excess dietary lipids are excreted with the feces.

High concentrations of unreabsorbed bile acids in the colon stimulate chloride secretion by the crypt cells. This leads to a secretory diarrhea.

6 Bilirubin Metabolism

• a. What is the major source of bilirubin?

• b. Is bilirubin protein bound inside the hepatocyte?

• c. Is there recycling of bilirubin from the intestine?

• d. When is jaundice observable?

• e. When does conjugated bilirubin levels become elevated in blood?

Age erythrocytes are taken up by the tissue macrophages. The heme portion is converted to bilirubin by heme oxygenase. In humans, most of the biliverdin is changed to bilirubin. Bilirubin in the circulation is albumin-bound. Upon entering the hepatocytes, the bilirubin becomes associated with cytoplasmic proteins.

Bilirubin is then conjugated to glucuronic acid in a 1:2 ratio in the smooth endoplasmic reticulum. The glucuronide is more water soluble and is actively transferred into the bile canaliculi. Some conjugated bilirubin leaks back into the blood and is excreted in the urine. Therefore total plasma bilirubin comprises free bilirubin and a small quantity of bilirubin glucuronide.

The intestinal mucosa is permeable to unconjugated bilirubin and urobilinogens, formed by intestinal bacteria. When free or conjugated bilirubin is retained in the blood, jaundice develops. Jaundice is seen when the plasma bilirubin exceeds 2 mg/100 ml (or 34 μmol/L). Hyperbilirubinemia can be associated with predominantly increased free or conjugated bilirubin. The former case is linked with hemolytic anemia, decreased hepatic uptake or defective glucuronide can regurgitate back into the circulation when there is interrupted secretion of conjugated bilirubin into the bile canaliculi. Intra-or extrahepatic bile duct obstruction also increases the plasma concentration of conjugated bilirubin.

7 Bile Flow

Comment on the following regarding bile secretions.

• a. Drugs that block bile acids reabsorption lower blood cholesterol.

• b. Bile is concentrated by the bile bladder epithelium.

• c. The bile acid pool is sufficient for a typical meal.

• d. The highest rate of gallbladder emptying takes place during the intestinal phase of digestion.

• e. The bile duct epithelium secrets an aqueous secretion.

Bile acids → excreted in the feces is the only significant pathway of cholesterol removal. Bile acids are synthesized by the hepatocytes from cholesterol. Thus agents that block the ileal reabsorption of bile acids will activate new synthesis of bile acids from cholesterol.

Between meals, bile is diverted into the gallbladder. The gallbladder concentrates the bile acid concentration 5 to 20-fold. Active transport of sodium is the mail active process in the concentrating action. The epithelia of the gallbladder have tight junctions and water absorption occurs by the standing osmotic gradient mechanism.

The strongest stimulus for gallbladder contraction is cholecystokinin. CCK relaxes also the sphincter of Oddi, which guards the entrance of the common bile duct into the duodenum. Normally, the rate of gallbladder evacuation is sufficient to keep the concentration of bile acids in the duodenum above the critical micelle concentration.

Bile acids emulsify fats to increase the surface area for digestion by pancreatic lipolytic enzymes. Bile acids then formed mixed micelles with the lipid digestion products. The transport of these products by the micelles to the epithelial brush border promotes the lipid absorption. Enterohepatic circulation occurs two to more times with a meal. About 10–20 % of bile acids escape absorption and is lost in the feces.

The aqueous secretion of the bile duct is isotonic and contributes about 50 % of the bile volume. The Na⁺ and K⁺ concentrations are similar to that in plasma. The HCO₃ ⁻ content is high and the hormone secretion stimulates this function of the bile duct.

8 Micelles and Lipid Digestion

• a. Of the classes of nutrients, which types are more prone to malabsorption?

• b. How much of intact triglycerides is found in micelles?

• c. Does the enterocyte make chylomicrons in the absence of luminal fat?

• d. Can triglyceride be hydrolyzed in the absence of bile acids?

• e. In the absence of pancreatic lipases, why are all classes of lipids poorly absorbed?

The digestion and absorption of lipids are more complex than for other classes of food. Thus malfunction of lipid absorption is more frequently accounted.

Mixed micelles are formed by lipid digested products and bile salts. The two major constituents are lysophosphatides and α-monoglycerides. In the hydrophobic intense of the micelle, extremely non-polar molecules like fat-soluble vitamins, cholesterol and long chain fatty acids tend to partition. Hardly any undigested triglyceride is sequestrated in the micelle.

Chylomicrons are not formed in the absence of fats in the diet. However, the enterocytes do make very-low density lipoproteins (VLDL) and extrude them into the intestinal lymph. VLDL has less triglycerides (60 % of VLDL mass) and more protein. They are more dense than chylomicrons.

Even when bile acids are not available, up to 50 % the normal fatty acid absorption from triglycerides can occur. Cholesterol and fat-soluble vitamins absorption are more severely affected by the absence of bile acids. Pancreatic insufficiency is also a cause of lipid malabsorption. This is probably due to the lack of building blocks for assembling the lipid micellar carrier. Lysophosphatides and 2-MG are both products of pancreatic lipase enzymatic activity.

9 Intestinal Epithelial Handling of Lipids

• a. How is fatty acids transported in the cytosol of the enterocyte?

• b. Why is chylomicron absorbed into the lacteals instead of the portal circulation?

• c. What contributes mainly to the mass of chylomicrons?

• d. Why does chylomicron vary so much in size?

• e. What molecule makes up most of the chylomicron surface?

Lipid resynthesis occurs in the intestinal epithelial cells before they are absorbed. This takes place in the smooth endoplasmic reticulum. The SER becomes engorged with lipids after a meal. Fatty acid-binding proteins (FABP) function to transport products of lipid digestion from the brush border to the SER. One type of FABP binds long-chain fatty acids. The other type of FABP has a broader specificity and carries also cholesterol, monoglycerides and lyophosphatides. There are also sterol carrier proteins. The re-esterification of 2-MG and lysophospholipids is virtually complete. Fatty acids with less than 10–12 carbon atoms can enter the portal blood as free, unesterified fatty acids.

The prechylomicrons from the SER are moved to the Golgi apparatus and further processed to chylomicrons. The chylomicrons are extruded by exocytosis. The remaining 20 % are taken up by the apolipoproteins. Most of the weight of the chylomicrons (90 %) comprise triglycerides which occupy the core of the chylomicron peptide. Cholesterol and cholesterol esters are found together with the TG and represents a small 1 % of chylomicron mass.

The size of the chylomicron depends on the amount of lipids that are absorbed. Chylomicron sizes vary from 60 to 750 nm in diameter. Chylomicrons are too large to transverse the basement membrane of the mucosal capillaries. In the lacteals, there are large fenestrations that the chylomicrons can enter through. Chylomicrons are drained by the lymphatic flow via the thoracic duct into the venous circulation.

10 Bile Acid Absorption and Secretion

• a. Is the intestinal absorption active or passive?

• b. Does bile contain primary or secondary bile acids?

• c. What is the effect of bile acids in the portal blood on hypatocyte bile acid synthesis?

• d. What are the constituents of gallstones?

• e. Bile acids are secreted into canaliculi down its concentration gradient. Comment.

Conjugated bile acids are actively absorbed at the terminal ileum by a Na⁺-bile salt cotransport basolateral Na⁺/K⁺ ATPase system. Bacteria in the terminal ileum and colon deconjugate bile acids and also dehydroxylate them to secondary bile acids. These two reactions reduce the polarity of bile acids and they can also be absorbed by simple diffusion. The hepatocytes reconjugate the bile acids normally with glycine or taurine. Rehydroxylation also occurs. The uptake and resecretion of bile acids by hepatocytes is stimulated by the reabsorbed bile acids in the enterohepatic cycling. This choleretic effect is associated with inhibition of new bile acid synthesis. Ileal resection increases the de novo synthesis of bile acids.

If the bile is supersaturated with cholesterol, the excess that is not solubilized in the micelles tend to crystallize. The most common variety of gallstone is cholesterol gallstones. Bile pigment gallstones can also form. This is mainly the insoluble calcium salts of unconjugated bilirubin. In liver disease, hepatocytes may be poor in making glucuronides of bilirubin.

Bile acids are secreted probably by facilitated diffusion. The concentration gradient is partly maintained by micellar formation in the canaliculi. This keeps the free concentration in solution quite low (critical micelle concentration).

The digestion and absorption of fats in the watery medium of the intestinal lumen requires the essential role of bile salts secreted in gall bladder bile when it contracts during a meal as fatty chyme enters from the stomach. The bile salts form mixed micelles which serve to solubilize the products of lipolysis and also to traffic them in these micelles to the absorptive epithelium. Micelles are not absolutely required for assimilation of lipids as fatty acids and monoglycerides have sufficient aqueous solubility to diffuse across the epithelium. However, fat soluble vitamins and cholesterol can’t diffuse by ‘themselves and need micelles’!

The release of duodenal secretin or cholecystokinin (CCK) is physio-logically regulated by a homeostatic feedback loop. For secretin, this is acid > Secretin > bicarbonate >neutralize acid. For CCK, the circular feedback sequence is protein/lipids > CCK > protease/lipase > proteo/lipolysis.

The hormone cholecystokinin (CCK) has a dual action on the gallbladder and pancreatic acinar cells. Bile and an enzyme-rich pancreatic secretion are released by CCK respectively. The bile salts in a fatty collaboration with pancreatic lipase act and digest dietary triglycerides.

Billy is a responsiBile character who lives in the green Gall Uplands. He comes down to the Duodenum Valley occasionally and helps to transport the fat people there.