Protein Digestion and Amino Acid Absorption

• Proteases (proteolytic enzymes) break down dietary proteins into peptides and then their constituent amino acids in the stomach and intestine.
• Pepsin initiates protein breakdown in the stomach.
• Upon entering the small intestine, inactive zymogens secreted from the pancreas are activated to continue protein digestion.
• Enzymes produced by the intestinal epithelial cells are also required to fully degrade proteins.
• The amino acids generated by proteolysis in the intestinal lumen are transported into the intestinal epithelial cells, from which they enter the circulation for use by the tissues.
• Transport systems for amino acids are similar to transport systems for monosaccharides; both facilitative and active transport systems exist.
• There are a large number of overlapping transport systems for amino acids in cells.
• Protein degradation (turnover) occurs continuously in all cells.
• Proteins can be degraded by lysosomal enzymes (cathepsins).
• Proteins are also targeted for destruction by being covalently linked to the small protein ubiquitin.
• The ubiquitin-tagged proteins interact with the proteosome, a large complex designed to degrade proteins to small peptides in an adenosine triphosphate–dependent process.
• Amino acids released from proteins during turnover can be used for the synthesis of new proteins, for energy generation, or for gluconeogenesis.

Integration of Carbohydrate and Lipid Metabolism

• Three key controlling elements determine whether a fuel is metabolized or stored: hormones, concentration of available fuels, and energy needs of the body.
• Key intracellular enzymes are generally regulated by allosteric activation and inhibition, by covalent modification, by transcriptional control, and by degradation.
• Regulation is complex in order to allow sensitivity and feedback to multiple stimuli so that an exact balance can be maintained between synthesis of a product and need for the product.
• The insulin/glucagon ratio is responsible for the hormonal regulation of carbohydrate and lipid metabolism.

Cholesterol Absorption, Synthesis, Metabolism, and Fate

• Cholesterol regulates membrane fluidity and is a precursor of bile salts, steroid hormones (such as estrogen and testosterone), and vitamin D.
• Cholesterol, because of its hydrophobic nature, is transported in the blood as a component of lipoproteins.
• Within the lipoproteins, cholesterol can appear in its unesterified form in the outer shell of the particle or as cholesterol esters in the core of the particle.
• De novo cholesterol synthesis requires acetyl coenzyme A as a precursor, which is initially converted to β-hydroxy-β-methylglutaryl-coenzyme A (HMG-CoA). The cholesterol synthesized in this way is packaged, along with triglyceride, into very low density lipoprotein in the liver and released into circulation.
• The conversion of HMG-CoA to mevalonic acid, catalyzed by HMG-CoA reductase, is the regulated and rate-limiting step of cholesterol biosynthesis.
• In the circulation, the triglycerides in very low density lipoproteins are digested by lipoprotein lipase, which converts the particle to intermediate-density lipoprotein and then to low-density lipoprotein.
• Intermediate- and low-density lipoprotein bind specifically to receptors on the liver cell, are internalized, and the particle components recycled.
• A third lipoprotein particle, high-density lipoprotein, functions to transfer apolipoprotein E and apolipoprotein C-II to nascent chylomicrons and nascent very low density lipoprotein.
• High-density lipoprotein also participates in reverse cholesterol transport, the movement of cholesterol from cell membranes to the high-density lipoprotein particle, which returns the cholesterol to the liver.
• Atherosclerotic plaques are associated with elevated levels of blood cholesterol levels. High levels of low-density lipoprotein are more strongly associated with the generation of atherosclerotic plaques, whereas high levels of high-density lipoprotein are protective because of their participation in reverse cholesterol transport.

Synthesis of Fatty Acids, Triacylglycerols, Eicosanoids, and the Major Membrane Lipids

• Fatty acids are synthesized mainly in the liver, primarily from glucose.
• Glucose is converted to pyruvate via glycolysis, which enters the mitochondrion and forms both acetyl coenzyme A and oxaloacetate, which then forms citrate.
• The newly synthesized citrate is transported to the cytosol, where it is cleaved to form acetyl coenzyme A, which is the source of carbons for fatty acid biosynthesis.
• Two enzymes, acetyl coenzyme A carboxylase (the key regulatory step) and fatty acid synthase, produce palmitic acid (16 carbons, no double bonds) from acetyl coenzyme A. After activation to palmitoyl coenzyme A, the fatty acid can be elongated or desaturated (adding double bonds) by enzymes in the endoplasmic reticulum.
• The eicosanoids (prostaglandins, thromboxanes and leukotrienes) are potent regulators of cellular function and are derived from polyunsaturated fatty acids containing 20 carbon atoms.
• Fatty acids are used to produce triacylglycerols (for energy storage) and glycerol phospholipids and sphingolipids (for structural components of cell membranes).
• Liver-derived triacylglycerol is packaged with various apolipoproteins and secreted into the circulation as very low density lipoprotein.
• As with dietary chylomicrons, lipoprotein lipase in the capillaries of adipose tissue, muscle, and the lactating mammary gland digests the triacylglycerol of very low density lipoprotein, forming fatty acids and glycerol.
• Glycerophospholipids, synthesized from fatty acyl CoA and glycerol 3-phosphate, are all derived from phosphatidic acid. Various head groups are added to phosphatidic acid to form the mature glycerol phospholipids.
• Phospholipid degradation is catalyzed by phospholipases.
• Sphingolipids are synthesized from sphingosine, which is derived from palmitoyl coenzyme A and serine. Glycolipids, such as cerebrosides, globosides, and gangliosides, are sphingolipids.
• The sole sphingosine-based phospholipid is sphingomyelin.

Digestion and Transport of Dietary Lipids

• Triacylglycerols are the major fat source in the human diet.
• Lipases (lingual lipase in the saliva and gastric lipase in the stomach) perform limited digestion of triacylglycerol prior to entry into the intestine.
• Cholecystokinin is released by the intestine as food enters, which signals the gallbladder to release bile acids and the exocrine pancreas to release digestive enzymes.
• Within the intestine, bile salts emulsify fats, which increases their accessibility to pancreatic lipase and colipase.
• Triacylglycerols are degraded to form free fatty acids and 2-monoacylgylcerol by pancreatic lipase and colipase.
• Dietary phospholipids are hydrolyzed by pancreatic phospholipase A2 in the intestine.
• Dietary cholesterol esters (cholesterol esterified to a fatty acid) are hydrolyzed by pancreatic cholesterol esterase in the intestine.
• Micelles, consisting of bile acids and the products of fat digestion, form within the intestinal lumen and interact with the enterocyte membrane. Lipid-soluble components diffuse from the micelle into the cell.
• Bile salts are resorbed farther down the intestinal tract and returned to the liver by the enterohepatic circulation.
• The intestinal epithelial cells resynthesize triacylglycerol and package them into chylomicrons for release into the circulation.
• Once in circulation the nascent chylomicrons interact with high-density lipoprotein particles and acquire two additional protein components; apolipoproteins C-II and E.
• ApoCII activates lipoprotein lipase on capillary endothelium of muscle and adipose tissue, which digests the triglycerides in the chylomicron. The fatty acids released from the chylomicron enter the muscle for energy production or the fat cell for storage. The glycerol released is metabolized only in the liver.
• As the chylomicron loses triglyceride, its density increases, and it becomes a chylomicron remnant. Chylomicron remnants are removed from circulation by the liver through specific binding of the remnant to apolipoprotein E receptors on the liver membrane.
• Once in the liver the remnant is degraded, and the lipids are recycled.