Lippincott's Biochemistry Chapter 15 - Dietary Lipid Metabolism PDF

UNIT III: Lipid Metabolism Dietary Lipid Metabolism I. OVERVIEW FATTY ACIDS Lipids are a heterogeneous group of water-insolubl...

UNIT III: Lipid Metabolism Dietary Lipid Metabolism I. OVERVIEW FATTY ACIDS Lipids are a heterogeneous group of water-insoluble (hydrophobic) organic molecules (Fig. 15.1 ). Because of their insolubility in aqueous c -o- ,, solutions, body lipids are generally found compartmentalized, as in the 0 case of membrane-associated lipids or droplets of triacylglycerol in adi- TRIACYLGLVCEROL pocytes, or transported in blood in association with protein, as in lipo- 0 protein particles (seep. 227) or on albumin. Lipids are a major source 9 9'"'2-0-c" of energy for the body, and they also provide the hydrophobic barrier ,,. c -o- c -H 0 that permits partitioning of the aqueous contents of cells and subcellular c'"'2-o-c structures. Lipids serve additional functions in the body (for example, some fat-soluble vitamins have regulatory or coenzyme functions, and QLYCEROPHOSPHOLIPID the prostaglandins and steroid hormones play major roles in the control 0II of the body's homeostasis). Deficiencies or imbalances of lipid metabo- \_ 9 yH2-0-C lism can lead to some of the major clinical problems encountered by c -o -c -H o I 1, + CH2- 0 -P- O·CH~tiaN (CHa)a physicians, such es atherosclerosis, diabetes, and obesity. (r STEROID II. DIGESTION, ABSORPTION, SECRETION, AND UTILIZATION The average daily intake of lipids by U.S. adults is -78 g, of which >OO°k HO is triacylglycerol ([TAG], formerly called triglyceride [TG]), that consists of three fatty acids (FA) esterified to a glycerol backbone (see Fig. 15.1). The SPHINGOGLYCOLIPID remainder of the dietary lipids consists primarily of cholesterol, cholesteryl 0II esters, phospholipids, and nonesterified (free) FA (FFA). The digestion of c dietary lipids begins in the stomach and is completed in the small intestine. Hr,i' H O - CH2- 9 - 9 The process is summarized in Figure 15.2. Carbohydrate H H A. Digestion In the stomach Rgure 15.1 Lipid digestion in the stomach is limited. It is catalyzed by lingual Structures of some common classes lipase that originates from glands at the back of the tongue and gastric of lipids. Hydrophobie portions of Iha lipase that is secreted by the gastric mucosa. Both enzymes are rela- molecules are shown In orange. tively acid stable, with optimal pH values of 4 to 6. These acid lipases 173 174 15. Dietary Lipid Metabolism Dietary llpld CE,PL, TAG ~o :.:.-: j... ~ (unchan..-) \ ) MOunt ~ -:- 9 Cholet1tsrol HO Jb i R-C- 0 fNll8r8IMI CholHleryl eeter (CE) Cholealillrol SMALL INTESTfiE rir- ~ ~ llottt of the CE, PL, TAO, and eome ehort· and medium-chain fa~ acids : Bii& salts emulslfy, ~~~-~ I1 and pancreatic enzymes degrade dietary lipids. Glycerylphoaphorylcholln lilCRONS ~ \ I PRIMARY PRODUCTS (Ll:vllFH)\ Free fatty acid 0II ReHllll'~.. 2-Monoacylglycerol 9 yHa- O- C- R1 I ChOleeterol Ra- C - 0 - yH 9 ~ , Remaining plecee of PL I CHa- 0 - C- Rs "V Trtacytglycerol (TAG) 2-Monoacylglycerol Figure 15.2 Overview of lipid digestion. hydrolyze FA from TAG molecules, particularly those containing short- or medium-chain-length (::S12 carbons) FA such as are found in milk fat. Consequently, these /ipases play a particularly important role in lipid diges1ion in infants for whom milk fat is the primary source of cal- ories. They also become important digestive enzymes in individuals with pancreatic insufficiency such as those with cystic fibrosis (CF}. Ungual and gastric lipases aid these patients in degrading TAG mole- cules (especially those with short- to medium-chain FA} despite a near or complete absence of pancreatic lipase (see Section 0.1. below). B. Cystic fibrosis 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 reg- ulator (CFTR) protein that functions as a chloride channel on epith&- lium 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 II. Digestion, Absorp1ion, Secretion, and Utilization 175 these enzymes and supplementation with fat-soluble vitamins. [Note: Chollcacld CF also causes chronic lung infections with progressive pulmonary disease and male infertility.] OH c. Emulslflcatlon In the amall lnt8911ne C-N-CH,poO- The critical process of dietary lipid emulsification occurs in the duode- num. 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, HO"' H 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 Glycochollc acid (a conjugated blle Nit) (seep. 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 Figure 15.3 agents interact with the dietary lipid droplets and the aqueous duode- Structure of glycocholic acid. nal 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 lhe dietary TAG, cholesteryl esters, and phospholipids are enzy- matically degraded (digested) in the small intestine by pancreatic enzymes, whose secretion is hormonally controlled. 1. Trlacylglycerol degradation: TAG molecules are too large to be taken up efficiently by the mucosal cells (enterocytes) of the intes- tinal villi. Therefore, they are hydrolyzed by an estemse, pancreatic lipase, which preferentially removes the FA at carbons 1 and 3. The primary products of hydrolysis are, thus, a mixture of 2-monoacyl- glycerol (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, colipsse, also secreted by the pancreas, binds the lipase at a ratio of 1:1 and anchors it at the lipid-aqueous interface. Co/ipase restores activity to lipase in the presence of inhibitory substances like bile salts that bind the micelles. [Note: Co/ipase is secreted as the zymogen, procolipase, which is activated in the intestine by trypsin.] Ortistat, an antiobesity drug, inhibits gastric and pancreatic lipases, thereby decreasing fat absorption, resulting in weight loss. 2. Choleateryl ester degradation: Most dietary cholesterol is pres- ent in the free (nonesterified) form, with 10o/o-15% present in the esterified form. Cholesteryl esters are hydrolyzed by pancreatic cholestery/ ester hydrolase (cholesterol este1aSe), which produces cholesterol plus FFA (see Fig. 15.2). Activity of this enzyme is greatly increased in the presence of bile salts. 3. Phospholipid degradation: Pancreatic juice is rich in the proen- zyme of phospholipase A2 that, like procolipase, is activated by trypsin and, like cho/8stsry/ ester hydro/ass, requires bile salts for optimum activity. Phospholipase A2 removes one FA from carbon 176 15. Dietary Lipid Metabolism 2 of a phospholipid, leaving a lysophospholipid. For example, phosphatidylcholine (the predominant phospholipid of digestion) becomes lysophosphatidylcholine. The remaining FA at carbon 1 can be removed by lysophospholipase, leaving a glycerylphospho- ryl base (for example, glycerylphosphorylcholine, see Fig. 15.2) that may be excreted in the feces, further degraded, or absorbed. 4. Control: Pancreatic secretion of the hydrolytic enzymes that degrade dietary lipids in the small intestine is hormonally controlled (Fig. 15.4). Cells in the mucosa of the lower duodenum and jejunum produce the peptide hormone cholecystokinin (CCK), in response to the presence of lipids and partially digested proteins entering these regions of the upper small intestine. CCK acts on the gallblad- der (causing it to contract and release bile, a mixture of bile salts, phospholipids, and free cholesterol) and on the exocrine cells of the pancreas {causing them to release digestive enzymes). It also decreases gastric motility, resulting in a slower release of gastric contents into the small intestine (see p. 353). Other intestinal cells produce another peptide hormone, secretin, in response to the low pH of the chyme entering the intestine from the stomach. Secretin causes the pancreas to release a solution rich in bicarbonate that helps neutralize the pH of the intestinal contents, bringing them to the appropriate pH for digestive actMty by pancreatic enzymes. E. Absorption by enterocytes FFA, free cholesterol, and 2-MAG are the primary products of lipid diges-- tion in the jejunum. These, plus bile salts and fat-soluble vitamins (A, D, E, and K), form mixed micelles (that is, disc-shaped clusters of a mixture of amphipathic lipids that coalesce with their hydrophobic groups on the inside and their hydrophilic groups on the outside). Therefore, mixed micelles are soluble in the aqueous environment of the intestinal lumen (Fig. 15.5). These particles approach the primary site of lipid absorp- tion, the brush border membrane of the enterocytes. This microvilli-rich apical membrane is separated from the liquid contents of the intestinal lumen by an unstirred water layer that mixes poorly with the bulk fluid. Degradation of d[etary llplda The hydrophilic surface of the micelles facilitates the transport of the hydrophobic lipids through the unstirred water layer to the brush border membrane where they are absorbed. Bile salts are absorbed in the ter- Figure 15.4 minal ileum, with __ acyllransAwa _.:::..... ( !) Trtacylglycerol 0 0 II RC- er r rFatty~ CaA ~ syntfJetase > II RC - CoA Long-chain fatly acids CoA ATP AMP + PP1 ~ acyl CoA Cholal terol-...;.Acy!;.;.r.;. CaA;"-=;. ;.;·chohJ8tero/.;.;.;.;.=;.;. ;acyifratJ~=.,_=.;.C __ ;_. : a. ""'__ j!" -+ Figure 15.6 Assembly and secretion of chytomierons by intestinal mucosal cells. [Note: Short- and medium-chain-length fatty acids do not require incorporation into chylomicrons and directly enter into the blood.] CoA = coenzyme A; AMP = adenosine monophosphate; PP1 = pyrophosphate. 178 15. Dietary Lipid Metabolism 9MAL1. apo B--containing particles in the ER (see p. 228).] The lipoprotein INTESTINE particles are released by exocytosis from enterocytes into the lacte- als (lymphatic vessels in the villi of the small intestine). The pres- ence of these particles in 1he lymph after a lipid-rich meal gives it a Dietary lipids milky appearance. This lymph is called chyle (as opposed to chyme, (3J the name given to the semifluid mass of partially digested food that passes from the stomach to the duodenum), and the particles are named chylomicrons. Chylomicrons follow 1he lymphatic system to )~ the thoracic duct and are then conveyed to the left subclavian vein, ~ o where they enter 1he blood. The steps in the production of chylomi- crons are summarized in Figure 15.6. [Note: Once released into blood, Biie the nascent (immature) chylomicrons pick up apolipoproteins E and C-11 from high-density lipoproteins and mature. (For a more detailed ~~ description of chylomicron structure and metabolism, see p. 227.)] D Pllncredc Juice Del'ectlv9 cell I. Use by the tissues Most of 1he TAG contained in chytomicrons is broken down in 1he capil- o