Lipid Digestion and Absorption

Group 7 Section A: Section B: Andico, Bastian, Cabonita, Eliseo, Jardenico, Lorea, Mendez, Pe Benito, Saripullah, Untalan

FAT DIGESTION - The mechanical phase includes chewing and grinding peristalsis in the stomach, which together create an emulsion with large fat droplets being sheared into smaller droplets. When chyme enters the small intestine, bile is added. Bile salts reduce surface tension at the fat droplet and water interface and further aid the formation of a fine emulsion. The chemical phase of fat digestion occurs when lipases remove fatty acids from the triglyceride molecules. Lipases are termed as acid or alkaline lipases, based on their pH optimum. Lingual lipase from the salivary glands and gastric lipase from the fundus of the stomach are acid lipases with a pH optimum between 3.5 and 5.5. In adults, acid lipases account for about 20% of total lipolysis, but in neonates this can be over 50% of the total lipolytic activity. Alkaline lipase is secreted by the pancreas and has a pH optimum between 6 and 8. The action of pancreatic lipase on triglycerides produces a monoglyceride and two free fatty acids. Pancreatic lipase requires colipase to effectively hydrolyze fats. Colipase is secreted by the pancreas and acts at the surface of a micelle by displacing a bile salt molecule, thereby providing a binding site for pancreatic lipase. Long-chain fatty acids produced by the action of pancreatic lipase are insoluble in water and must enter the core of a micelle to be dissolved. Other lipases include phospholipase A2, which degrades lecithins and other phospholipids, and carboxyl ester lipase (nonspecific lipase), which is able to hydrolyze cholesterol esters. Lingual and Gastric (Acid) Lipase Initiate Lipid Digestion A small amount of lipid digestion begins in the mouth, mediated by lingual lipase. In the stomach, both lingual lipase that is swallowed and a gastric lipase secreted by gastric chief cells digest substantial amounts of lipid. Human gastric lipase is a 42-kDa glycoprotein whose secretion is stimulated by gastrin. Gastric lipase secretion is already well established in the neonatal period (unlike pancreatic lipase secretion), and thus gastric lipolysis is important for fat digestion in newborn infants. Gastric and lingualas well as pharyngeal-lipases belong to a family of serine hydrolases that have acidic pH optima (pH 4), are stable in the acidic environment of the stomach, are resistant to digestion by pepsin, and are not inhibited by the surface layer of membrane lipids (emulsifiers) that envelopes triglyceride droplets. However, acid lipases are readily inactivated by pancreatic proteases (especially in the presence of bile salts) once they reach the small intestine. Pancreatic Lipase:Lipolysis

Hydrolyzes triglyceride containing short chain and long chain fatty acids Complete hydrolysis of fat (trigylcerides) produces glycerol and fatty acids Specific for the hydrolysis of primary ester linkage

A major component of dietary fat is triglyceride, or neutral lipid. A triglyceride molecule cannot be directly absorbed across the intestinal mucosa. Rather, it must first be digested into a 2-monoglyceride and two free fatty acids. The enzyme that performs this hydrolysis is pancreatic lipase, which is delivered into the lumen of the gut as a constituent of pancreatic juice. Sufficient quantities of bile salts must also be present in the lumen of the intestine in order for lipase to efficiently digest dietary triglyceride and for the resulting fatty acids and monoglyceride to be absorbed. This means that normal digestion and absorption of dietary fat is critically dependent on

secretions from both the pancreas and liver. Process:

1. First, removal of a terminal fatty acid to produce ,-diglyceride; the other terminal fatty acid
is then removed to produce-monoglyceride 2. Since the last fatty acid at position Sn-2 is linked by a secondary ester group which cannot be easily hydrolyzed by pancreatic lipase, the -monoglyceride is first converted to -monoglyceride by isomerization by an isomerase enzyme 3. -monoglyceride is then hydrolyzed by pancreatic lipase 4. By the action of pancreatic lipase and isomerase, and monoglycerides are the major end products of fat digestion Less than of the ingested fat is completely broken down into: glycerol and fatty acid FAT ABSORPTION - Medium-chain fatty acids are able to freely diffuse from the intestinal lumen into the blood without modification; however, most triglyceride digestion produces long- chain fatty acids. Absorption occurs via the following steps: Long-chain fatty acids dissolve in micelles, which provide a means for hydrophobic molecules to diffuse through an unstirred fluid layer at the intestinal surface. The unstirred fluid layer has a lower pH than the neutralized chyme, which destabilizes micelles as they approach surface cells; long-chain fatty acids escape the micelle and enter the enterocyte by diffusion through the plasma membrane. Enterocytes convert long-chain fatty acids back into triglycerides within the smooth endoplasmic reticulum. Triglycerides are complexed with apoproteins within the smooth endoplasmic reticulum. The Golgi apparatus delivers the lipoprotein complexes in large vesicles called chylomicrons, which are transported across the basolateral membrane by exocytosis. Chylomicrons are too large to pass across the capillary endothelia and instead enter the lymphatic vessels. Chylomicrons enter the systemic blood when lymph drains into the venous system. The action of the enzyme endothelial lipoprotein lipase liberates fatty acids from chylomicrons, primarily for uptake by adipose tissue and muscle cells; the remnant chylomicrons are processed by the liver.

Lipid Absorption: Micellar transport Micellar transport of lipid breakdown products to the surface of the enterocyte. Mixed micelles carry lipids through the acidic unstirred layer to the surface of the enterocyte. 2-MAG, fatty acids, lysophospholipids, and cholesterol leave the mixed micelle and enter an acidic microenvironment created by an apical Na-H exchanger. The acidity favors the protonation of the fatty acids. The lipids enter the enterocyte by (1) nonionic diffusion, (2) incorporation into the enterocyte membrane (collision), or (3) carrier-mediated transport. Lipid Absorption: Re-esterification of digested lipids Re-esterification of digested lipids by the enterocyte and the formation and secretion of chylomicrons. The enterocyte takes up short- and medium-chain fatty acids and glycerol and passes them unchanged into the blood capillaries. The enterocyte also takes up long-chain fatty acids and 2-MAG and resynthesizes them into TAG in the SER. The enterocyte also processes cholesterol into cholesteryl esters and lysolecithin into lecithin.

Fate of these substances, and the formation of chylomicrons: 1. Long-chain fatty acids and other products of lipid digestion are converted back to triacylglycerols, phospholipids, and esters of cholesterol in the SER 2. Fat droplets form in the cisternae of the SER. 3. Apolipoproteins are synthesized in the RER and then (except for apolipoprotein A1) move to the SER, where they associate with lipid droplets. Apo A1 associates with chylomicrons in the Golgi apparatus. 4. Nascent chylomicrons and VLDLs arrive at the cis face of the Golgi apparatus. Here, apolipoproteins are glycosylated. 5. Vesicles carrying chylomicrons or VLDLs bud off from the trans-Golgi apparatus, and move to the basolateral membrane in transport vesicles. 6. Transport vesicles fuse with the basolateral membrane, releasing chylomicrons or VLDLs. 7. Chylomicrons and VLDLs pass through large interendothelial channels of lymphatic capillaries, and enter the lymph. 8. Glycerol, short-chain, and medium-chain fatty acids pass through the enterocyte and enter blood capillary. Lipid Transport and Utilizaton Lipoprotein functions:
Chylomicron - deliver fatty acids as part of TAG, from dietary fat to muscle and adipose tissues Chylomicron remnants - deliver dietary cholesterol to the liver VLDL - deliver fatty acids, attached to TAG, derived from liver synthesis to non-hepatic tissues

(e.g., muscle, adipose) LDL - from VLDL; delivers cholesterol, derived from liver synthesis to various tissues HDL - collects cholesterol from non-hepatic tissues and delivers to the liver Apoproteins and their characteristics: Chylomicron
Apo B-48 - chylomicron formation Apo CII - activates lipoprotein lipase Apo E - transferred to remnants

Chylomicron remnants
Apo E - binds to liver receptor for chylomicron remnants to enter the cell

VLDL
Apo B-100 - assembly of VLDL Apo CII - activates lipoprotein lipase Apo E - binds to liver receptor for VLDL to enter the cell

LDL
Apo B-100 - binds to LDL receptor for LDL to enter the cell

HDL
Apo A1 - facilitates cholesterol efflux from cells Apo CII - stored on HDL for transfer to chylomicrons and VLDL Apo E - binds to liver receptor for HDL to enter the cell

Transport and processing of lipids in the exogenous system The exogenous system includes chylomicrons, chylomicron remnants and to a small extent HDL. Chylomicrons are distributed into the body through the lymphatic system to various non-hepatic tissues, primarily adipose tissue and muscle. The chylomicrons must deliver fatty acids (from the TAGs) to these tissues. Process:
Apoprotein B-48 forms a shell around the lipids to facilitate formation of the chylomicron. The

surface protein is hydrophilic to aid in solubilization of the chylomicrons. From the lymphatics, chylomicrons enter the capillaries of target tissues. Apoprotein CII activates the lipoprotein lipase molecules. Lipoprotein lipase, attached to the inner wall of the capillaries, catalyzes the hydrolysis of the TAGs to release fatty acids that enter the tissues. After their release from the TAGs, the fatty acids traverse the cell membrane to be taken up by the tissue. Chylomicron remnants containing largely of dietary cholesterol is taken in by the liver by binding of apoprotein E to receptors on the surface of the liver. Transport and processing of lipids in the endogenous system The endogenous system involves three lipoproteins VLDL, LDL and HDL. VLDL is formed in the liver from TAG and cholesterol provided by the tissue and with the assistance of apoprotein B-100.

The VLDL is exported and picks up apoprotein CII and E in the blood. VLDL molecule contains the apoproteins needed for both VLDL and LDL functions. The role of VLDL is to transport and deliver fatty acids to peripheral tissues. TAGs contained in VLDL, are substrates for lipoprotein lipase in capillaries. Through apo CII, fatty acids synthesized from excess sugar in liver, are delivered to other tissues.

After TAG hydrolysis by lipoprotein lipase, VLDL converts to the LDL. The density increases because of the loss of the TAGs. The role of LDL is to carry cholesterol, derived from the liver, to other tissues. LDL travels through the blood to a variety of tissues. Apo B100, on the LDL particle, binds to LDL receptors on the tissues, and LDL deposits its cholesterol in the cell.

Finally, HDL contains the smallest percentage of lipids and benefits the body by being a scavenger of cholesterol from peripheral tissues.
HDL contains apo A1 that facilitates the formation of cholesterol ester, via an acyltyransferase

(LCAT). It is cholesterol ester that is stored in the core of the HDL particle. HDL attaches to liver cell receptors via its apo E protein, analogous to the chylomicron remnants. Higher levels of HDL and a greater ratio of HDL:LDL can be protective against the deleterious effects of excess cholesterol. Individuals with a lower than normal ratio of HDL:LDL should receive appropriate treatment through diet modification and/or inhibition of cholesterol biosynthesis in the body. Hormones regulate fat mobilization The rate of release of free fatty acids from adipose tissue is affected by many hormones that influence either the rate of esterification or the rate of lipolysis. Hormone that inhibits lipolysis: INSULIN
inhibits the release of free fatty acids from adipose tissue enhances lipogenesis and the synthesis of acylglycerol dependent on the presence of glucose (uptake of glucose into adipose cells via the GLUT 4

transporter) increases the activity of pyruvate dehydrogenase, acetyl-CoA carboxylase, and glycerol phosphate acyltransferase, reinforcing the effects of increased glucose uptake on the enhancement of fatty acid and acylglycerol synthesis A principal action of insulin in adipose tissue is to:
inhibit the activity of hormone-sensitive lipase by inhibiting the synthesis of cAMP at the

adenylyl cyclase site, acting through a G protein stimulate phosphodiesterase and the lipase phosphatase that inactivates hormone-sensitive lipase Hormones that promote lipolysis: 1. 2. 3. 4. 5. 6. 7. 8. Epinephrine Norepinephrine Glucagon Adrenocorticotropic hormone (ACTH) Melanocyte-stimulating hormones (MSH) Thyroid-stimulating hormone (TSH) Growth hormone (GH) Vasopressin

These hormones accelerate the release of free fatty acids from adipose tissue and raise the plasma

free fatty acid concentration by increasing the rate of lipolysis of the TAG stores. Many of these activate hormone-sensitive lipase. Lipolytic processes require the presence of glucocorticoids and thyroid hormones. These hormones act in a facilitatory or permissive capacity with respect to other lipolytic endocrine factors. How these hormones promote lipolysis:
By stimulating the activity of adenylyl cyclase

 Through cAMP, by stimulating cAMP-dependent protein kinase, activating hormone-sensitive

lipase