Corrected by. numb. Done. Doctor. Asma Karameh. Faisal Al Khateeb. 1 P age

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1 numb 27 Done Asma Karameh Corrected by ا لاء العجرمي Doctor Faisal Al Khateeb 1 P age

DIGESTION AND TRANSPORT OF TRIACYL-GLYCEROL BY PLASMA LIPOPROTEIN General Lipids refer to a collection ofheterogeneous molecules of varying composition and a great range of functions in metabolic and

Uponformation of TAG, the esterification of the carboxyl group of fatty acids with hydroxyl groups of glycerol decreases the hydrophilicity of both fatty acids and glycerol ( esters are less polar

2 DIGESTION AND TRANSPORT OF TRIACYL-GLYCEROL BY PLASMA LIPOPROTEIN General Lipids refer to a collection ofheterogeneous molecules of varying composition and a great range of functions in metabolic and physiologic processes. Their common property is insolubility in water and solubility in organic solvents. Uponformation of TAG, the esterification of the carboxyl group of fatty acids with hydroxyl groups of glycerol decreases the hydrophilicity of both fatty acids and glycerol ( esters are less polar than Alcohols). So ester bonds are nonpolar and can t interact with water. Phosphoacyl glycerol as Phosphoacylglycerols (which are diglycerides that consist of: glyceride+ (2) fatty acids + phosphoric acid) are amphipathic molecules which can act as emulsifiers because of the phosphate and the hydroxyl groups. Phosphoacylglycerols can form micelles which allow the mixing of TAG and water. In other words they allow packaging of TAG by increasing their solubility. How is Triacylglyceroltransported in the blood? 2 P age

3 After Dietary TAG molecules and other lipid components like cholesterol are absorbed, they are packaged into very large lipoproteins calledchylomicrons. These chylomicrons pass into the lymph and then into the blood in order to be delivered to tissues for utilizationand to prevent coalescence in aqueous solutions. Chylomicrons are very large lipoproteins. A lipoprotein (LP) is a biochemicalamphipathic assemblythat contains both lipids and proteins. The protein moiety (or polypeptide) is called Apo-lipo protein Apolipoproteins appear as a thin layer enveloping the lipid droplets. The prefix APO indicates the protein part. Apo proteinsare divided into several classes (discussed next). Apolipoproteins serve different functions: 1. Structural they maintain the structure of lipoproteins. (Example: Apo- A and Apo- B) 2. Regulatory they interact with enzymes that metabolize lipoproteins 3. Binding with cell surface receptors mediate interactions with cells (they act as ligands for interaction with lipoprotein receptors in tissues. (Example:Apo B-100 and Apo E are ligands for LDL receptor, Apo A-1 is a ligand for the HDL receptor) 4. EnzymeCofactors.(Example: Apo-CII which is cofactor for lipoprotein lipase) 5. Lipid transfer carriers that regulate the metabolism of other lipoproteins and theiruptake. In tissueslipoproteins allow fats to move through water inside and outside cells. In other words they emulsify the lipid molecules. Typical water-micelle lipoproteinparticles associate nonpolar lipids (TAG and cholesterylesters) which form the core of lipoproteins, with amphipathic lipids (phospholipids and cholesterol) which form the single surface layer and proteins. 3 P age

Some lipoproteins are integraland can t be removed such as Apo-A & B, whereas others can be freely transferred to other lipoproteins known as peripheral lipoproteinssuch as Apo E, Apo-C I, APO-CII,

1) Classification based on density: For this type of classification, we use ultracentrifugation.

4 Some lipoproteins are integraland can t be removed such as Apo-A & B, whereas others can be freely transferred to other lipoproteins known as peripheral lipoproteinssuch as Apo E, Apo-C I, APO-CII, and APO C-III. Classification of lipoproteins differs in the ratio of protein to lipids and in the particular Apo proteins and lipids that they contain. 1) Classification based on density: For this type of classification, we use ultracentrifugation. Ultracentrifugation: benefiting from the centrifugal force using an expensive machine (alpha centrifuge المركزي (الطرد for sedimentation of heterogeneous mixtures. At a very high speed more-dense components migrate away from the axis of the centrifuge while less-dense components migrate towards the axis. For a clearer vision dyes are used to interact with lipids (the same step is applied with separation of plasma proteins with different dyes interacting with proteins). Depending on the ratio of lipids to proteinand density, five major groups of lipoproteins have been identified: 1. Very low density lipoproteins (VLDP): the second highest in TAG. 2. Chylomicrons: The largest, the lowest in density due to high lipid/ protein ratio, highest content of TAG (90%) and they are responsible for the transport of all dietary lipids into the circulation. 3. Intermediate density lipoprotein IDL: derived from catabolism of VLDL with a density ranging between very low density and low density lipoproteins. 4 P age

5 4. HDL: highest in density lipoprotein due to low lipid/protein ratio, involved in cholesterol transport and also invldl and chylomicron metabolism. 5. LDL: low density lipoprotein, highest in cholesteryl esters. Notice: Thedensity is also relative to the type of lipids carried, e.g. Chylomicrons have very high content of TAG which have much lower density than water and cholesterol. More than 70% of lipids in HDL and IDL are AMPHIPATHIC molecules (free cholesterol and phospholipids) found on the surface. While in chylomicrons most of the lipids are nonpolar molecules (TAG and cholesterol esters) forming the inside core. This is important in determining the percentage of therelative surface components, which is higher in HDL and LDL. As the percentage of surface components relatively increases, the size relatively decreases.so the chylomicrons have the largest size (relative to the size of small cells). Lipoproteins with high lipid content will have low density, and a larger size, so they float in centrifugation, while those with high protein content sediment easily, have a compact size and a high density. 5 P age

2) ClassificationBased on electrophoretic motilities: Lipoproteins contain ionisable groupsjust likeproteins and nucleic acids, therefore at any given PH they exit in

Under the influence of an electrical field cations migrate to the cathode (the negative electrode) or anions move to the anode (the positive electrode).

Net charge doesn t only include the value of the charge but also mostly depends on the number of the charged amino acids in the protein moiety.

6 2) ClassificationBased on electrophoretic motilities: Lipoproteins contain ionisable groupsjust likeproteins and nucleic acids, therefore at any given PH they exit in the solution as electrically charged species, either as anions (-) or cations (+). Under the influence of an electrical field cations migrate to the cathode (the negative electrode) or anions move to the anode (the positive electrode). In lipoproteins, protein moiety is the source of the charge, so as protein content increases, the net charge increases, and mobility is greater. Net charge doesn t only include the value of the charge but also mostly depends on the number of the charged amino acids in the protein moiety. Electrophoresis separation isn t based on density. But based on the combination between size and net charge. According to their electrophoretic properties lipoproteins are grouped into:alpha, prebeta, beta, and broadbetalipoproteins. The mobility of a lipoprotein is mainly dependent on protein content. 6 P age

$Free fatty acids and albumin complex (although not a lipoprotein) is an important fraction in serum and is the fastest moving fraction.$

7 Those with higher protein content will move faster toward the anode (- ), and those with minimum protein will have minimum mobility. Free fatty acids and albumin complex (although not a lipoprotein) is an important fraction in serum and is the fastest moving fraction. Chylomicrons remain at the origin since they have more lipid content. VLDL with less protein content than LDL move faster. This is due to the nature of Apo protein Comment [sk1]: As the lipid content increases, density decreases and size increases. That is why chylomicrons are least dense but biggest in size. While HDL are rich in proteins, most dense, but smallest in size. 3) Classification based on nature of Apo-protein content: The major Apolipoproteins in HDL (alpha-lipoprotein) are designated A. The main Apolipoproteins of LDL (Beta-lipoprotein) areapolipoprotein (B- 100) which is also found in VLDL. Chylomicrons contain Apo-(B-48). The amino acid sequence of Apo (B- 48) represents 48% of the initial sequence of apob-100. They are synthesized from the same gene. (ApoB-48) is synthesized only by the intestines in humans, while apob- 100 is synthesized primarily by the liver. 7 P age

8 Apo-Eis a peripheral apolipoproteinfound invldl, HDL, and Chylomicrons. It is important to consider that separation and differentiation between the different types of lipoproteins have a great clinical importance in which many diagnoses are based on the percentage of these molecules in serum. Digestion of dietary lipids Major dietary lipids are TAG, phospholipids and esterified cholesterol. Dietary lipids have to be hydrolysed before their absorption from the alimentary tract. Digestion of lipids involves hydrolysis of ester bonds. Digestion of cholesterol esters produces cholesterol and fatty acids. (Mainly by cholesterol esterase). Digestion of TAG results in production of two fatty acids, and a glycerol associated with one fatty acid (2-monoacyl glycerol). This conversion occurs by salivary lipase. Keep in mind that TAGs are too large to be absorbed directly by blood capillaries. Hydrolysis reactions occur in the aqueous environment of the digestive tract, by lipases that only work on the surface of fat globules. So in order for lipids to be able to interact with water molecules (breaking their solubility border), Emulsification is important. Emulsification:breaking fatglobules into smaller emulsion droplets in the small intestinein order to increase solubility of dietary lipids. Emulsification occurs by detergent property of bile salts and peristalsis. With molecules found in the Bile that are similar to cholesterol (because they are derivatives of cholesterol)known as bile acids,mixing or interaction between hydrophobic fats and soluble lipases becomespossible. So Bile acids are: 1) Amphipathicmolecules. 8 P age

2) Cholesterolderivatives. 3) Weakbacids. 4) Having two or more hydroxyl groups.

ycine or any other amino acids containings

9 2) Cholesterolderivatives. 3) Weakbacids. 4) Having two or more hydroxyl groups. If bile acids get conjugated in the liver withglycine or any other amino acids containingsulfergroups(e.g. TAURINE) the molecule becomes a stronger acid and they form potassium and Sodium salts in the bile ( Bile salts ) and as mentioned they are important detergents for complete lipid digestion. 1. Digestion in mouth: Saliva contains the lingual lipase, which is secreted by the dorsal surface of the tongue. It remains in the mouth for a short time then enters the stomach along with food. The lingual lipase remains active even in the acidic environment of stomach. In other words it is active at low PH (2-7.5) Lingual lipase acts preferentially on TAG containing short or medium-chain fatty acids. 9 P age

digestion, which are absorbed directly from stomach wall and enters portal vein. The action of lingual lipase is more significant in new-borns. 2.

10 (Ideal substrate). And the ester bond at position 3. The rate oflong-chain fatty acid digestion in mouth is slow because fat is not yet emulsified (its efficacy is far less than pancreatic lipase) Short chain FAs are released as end products of digestion, which are absorbed directly from stomach wall and enters portal vein. The action of lingual lipase is more significant in new-borns. 2. Digestion in the stomach: Lingual lipase also works in the stomach Another lipase which is the gastric-lipase is secreted in small quantities but it is more effective at alkaline (average PH 7.8) and it digests up to 30% of TAG. Notice: lingual and gastric lipases are both acid stable not destroyed by the high acidity of the stomach and they have optimum PH in the acidic PH of the stomach. Most effective for short and medium- chain fatty acids (milk, egg yolk, and TAG), so they are more essential for neonates. Short and medium chain fatty acids are digested rapidly before reaching the small intestines. SO they are absorbed directly into the enterocytes and then to portal circulation. Lingual and gastric lipases are important digestive enzymes in pancreatic insufficiency (unable to produce adequate lipases) Such as cystic fibrosis, or other pancreatic disorders. Lingual and gastric lipases can degrade TAG with short or medium chain fatty acids in patients with pancreatic disordersdespite a near or complete absence of pancreatic lipase. 3. Emulsification and digestion in the intestines: 10 P age

11 Emulsification is prerequisite for digestion of lipids. Pancreatic enzymes in the intestines are the major digestive ones of dietary lipids e.g. 1) Pancreatic lipaseforcomplete digestion of TAG with long chain fatty acids to produce 2-monoacyl glycerol + 2 fatty acids. 2) Phospholipase A2for digestion of phospholipids to produce lysophospholipids + fatty acids 3) Cholesterol esteraseto digest cholesterol esters and producing cholesterol All these products form what is called mixed micelles because they can go through intestines when they become in contact with intestinal mucosal cells (the products of digestion can diffuse through the intestinal cells) By emulsification, which occurs mainly in the duodenum, lipids are dispersed into smaller droplets, reducing surface tension and increasing surface area for enhanced activity of the digestive enzymes. The process of emulsification is favoured by: a. Bile salts ( amphipathic molecules &detergent action) b. Peristalsis(mechanical mixing) c. Phospholipids (amphipathic molecules) Pancreatic lipase is specific for hydrolysis of primary ester linkages (fatty acids present at position 1and 3) Ester linkage at Position 2 can t be hydrolysed. Orlistat is an antiobesity drug that inhibits gastric and pancreatic lipases thereby decreasing lipid digestion and absorption resulting in weight loss. Bile acids and bile salts: Bile salts with pancreatic lipase are essential for effective digestion. 11 P age

12 Bile salts help in combininglipaseswith two molecules of small protein called colipaseto enhance the lipase activity. Bile salts are synthesized in the liver and stored in the gall bladder. Bile saltsconsist of sterol ring structure with a side chain to which a molecule of glycineor other sulfer containing amino acidsare attached. As mentioned, bile salts are synthesized from bile acids. The primary bile acids are cholicacids. Bile salts stabilize lipid particles as they become smaller and preventing them from coalescing. This requires activation of fatty acids to form fatty acyl COA. THE END 12 P age

Moh Tarek + Suhayb. Tamara Al-Azzeh + Asmaa Aljeelani ... Faisal

Moh Tarek + Suhayb. Tamara Al-Azzeh + Asmaa Aljeelani ... Faisal 28 Moh Tarek + Suhayb Tamara Al-Azzeh + Asmaa Aljeelani... Faisal Digestion of dietary lipids Lipid digestion and absorption are complex processes. They involve soluble enzymes, substrates with different