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Digestion of Fats (Triglycerides/Lipids) By: Brittany Speer, William McNees, Peter Schulz, Maiko Ibay, and Regina Tabi Chemical Structure of Fat Lipid is the general term which encompasses all different types of fat Lipids are further broken down into saturated and unsaturated A Triglyceride molecule is made up of one glycerol molecule and three fatty acid chains Saturated The fatty acid chain consists of only single bonds, thus fully saturated with hydrogens Unsaturated Mouth The mouth is the first site of mechanical and chemical digestion Mechanical Digestion Physical Breakdown of food Occurs through the teeth, tongue, and palate Food is mixed with saliva to create a bolus No chemical digestion occurs in the mouth Esophagus Connects the pharynx to the stomach Responsible solely for motility Peristalsis Rhythmic, wave-like contractions that moves food through the digestive tract Moves the bolus at a rate of 2-4cm per second Food is emptied into the stomach through the gastroesophageal sphincter Constriction of this sphincter prevents stomach contents from regurgitating into the esophagus Stomach Functions of the stomach Storage of food Kill bacteria with the strong acidity of the gastric juices Contractions of the stomach cause the stomach to churn and mix the food substances with the gastric juices This combination is called chyme Continuation of mechanical digestion Small Intestine Chemical digestion of fats begins in the small intestine Chyme enters the upper portion of the small intestine called the duodenum This causes the gallbladder to contract and secrete bile into the duodenum through the bile duct The pancreas then secretes bicarbonate ions and enzymes Bicarbonate ions neutralize the pH of the chyme Emulsification by Bile Salts Bile salts are synthesized in the liver using cholesterol and regulated by bacteria Stored in the gall bladder Once secreted into the duodenum the bile salts surround the fat and break it into smaller droplets Surrounding the smaller droplets prevents the fat from reclumping Increases the surface area for the lipase to act upon the fat droplets Digestion by Enzymes Pancreatic Lipase digests triglycerides into its individual parts Long Chain fatty acids (>10 carbons): breaks down into a monoglyceride and two free fatty acids Short Chain fatty acids (<10 carbons): breaks down into glycerol and three free fatty acids Pancreatic Colipase Colipase is a protein co-enzyme that is required for optimal activity of pancreatic lipase Secreted by the pancreas in its inactive form and activated by trypsin in the duodenum Absorption ● Most fat absorption takes place in the duodenum or jejunum – micelles carry monoglycerides and free fatty acids to the brush border where they diffuse into enterocytes ● Bile salts are absorbed in the ileum (enterohepatic circulation) ● Once in the enterocytes, monoglycerides and free fatty acids are reformed into triglycerides ● The triglycerides, cholesterol, phospholipids, and protein carriers form LIPOPROTEIN Once these lipoproteins leave the cell, they become CHYLOMICRONS and enter the lymph system MCTs, short-chain fatty acids and glycerol are absorbed directly into bloodstream. They do not enter the lymph system. Small lipid fragments: ● Glycerol and short chain FAS (SCFAS) ● Absorbed directly into the bloodstream ● Portal vein to liver Big lipid fragments: ● Monoglycerides and LCFAs need help! If absorbed into the blood, they need to be emulsified Cholesterol Cholesterol and other sterols are poorly absorbed. Overall, about 50% of dietary cholesterol is absorbed. Dietary fat increases cholesterol absorption Fiber (especially soluble fiber) and phytosterols decrease cholesterol absorption High levels of low-density lipoprotein (LDL) cholesterol in the circulation increase the risk for the development of atherosclerosis Of the total cholesterol that passes through the small intestine, only half is typically absorbed, and the rest is eliminated in the feces. Cholesterol Biosynthesis Pathway The process to form the 27 carbon compound of cholesterol occurs primarily in 4 main stages. Stage 1: Synthesis of mevalonate from acetate Two molecules of acetyl-CoA condense, forming acetoacetyl-CoA, which condenses with a third molecule of acetyl-CoA to yield the six-carbon compound β-hydroxy-β-methylglutaryl-CoA (HMGCoA), which is then reduced to from mevalonate Generally takes place in the endoplasmic reticulum of hepatic cells! Cholesterol Biosynthesis Pathway Stage 2: Conversion of mevalonate to two activated isoprenes In this next stage, three phosphate groups are transferred from three ATP molecules to mevalonate., The phosphate attached to the C-3 hydroxyl group will leave and produce a double bond in the 5 carbon product. The two isoprenes are Δ3-isopentenyl pyrophosphate and dimethylallyl pyrophosphate Cholesterol Biosynthesis Pathway Stage 3: Condensation of six activated isoprene units to form squalene Isopentenyl phosphate and dimethylallyl phosphate undergo a “head-to-tail” condensation in which one phosphate group is displaced and a 10-carbon chain (geranyl phosphate) is formed. Another “head-to-tail” condensation→ 15-carbon farnesyl pyrophosphate Finally, two molecules of farnesyl join head to head, eliminating the phosphate groups and forming squalene Cholesterol Biosynthesis Pathway Step 4: Conversion of squalene to the four-ring steroid nucleus Squalene monooxygenase adds one oxygen atom from O2 which forms squalene-2,3-epoxide. Linear squalene epoxide can be converted into a cyclical structure→ Lanosterol (in animal cells)→ converted into cholesterol in a series of about 20 reactions Cholesterol Ester It is an ester of cholesterol Ester: chemical compound in which at least one hydroxyl group replaced by an alkyl group The ester bond is formed between the carboxylate group of a fatty acid and the hydroxyl group of cholesterol Lower solubility in water due to their increased hydrophobicity More cholesterol can be packaged in lipoproteins in this structure, so the body does this to be more efficient→ inactive transport form Lipoprotein Structure ● Membrane: ○ Single phospholipid layer ○ Protein ○ Cholesterol ● Core: ○ Triglyceride ○ Cholesterol ester ● Differences in various lipoproteins: Transportation of Lipids in Blood Chylomicrons: ● Phospholipids, cholesterol and triglycerides (resynthesized in E.R. of enterocytes) combine with protein to form chylomicrons ● 90% triglyceride, 4% phospholipid, 1% protein, 5% cholesterol ○ apo E ● Excreted into lacteals and circulate into the blood via thoracic duct ○ (lacteals -> lymphatic vessels -> thoracic duct -> left subclavian vein) ● Acquire apolipoprotein (Apo E) Transportation of Lipids in Blood Chylomicrons: ● Lipoprotein lipase enzyme hydrolyze triglycerides held within chylomicron ● Free fatty acids bind to albumin and circulate in plasma to be used by skeletal muscle and adipose tissue ● Remnant particles are released and circulate until taken up by liver Transportation of Lipids in Blood Very Low-Density Lipoprotein (VLDL) ● 60% triglyceride, 18% phospholipid, 8% protein, 14% cholesterol ○ apo B-100, apo C1, apo E -> picks up apo C-II and additional apo E during circulation ● Deliver endogenously produced triglycerides to extrahepatic cells ● Cholesterol and triglycerides produced in liver combine with other apolipoproteins to form VLDLs ● VLDLs circulate and bind to capillary cells, losing triglycerides along the way via receptor-mediated endocytosis Transportation of Lipids in Blood Low-Density Lipoprotein (LDL) ● 10% triglyceride, 20% phospholipid, 25% protein, 45% cholesterol, ○ apo B-100 ● Product of VLDL losing triglycerides ● Delivers endogenous cholesterol to various organs before returning to liver ● Contributes to atherosclerosis ● Familial Hypercholesterolemia ● Dyslipidemia (Hyperlipidemia) Transportation of Lipids in Blood High-Density Lipoproteins (HDLs) ● “Reverse Cholesterol Transport” ● 5% triglyceride, 30% phospholipid, 45% protein, 20% cholesterol ○ apo A-1 & apo A-2 ● Produced in peripheral tissues ● HDL binds to receptors in vessel walls of extrahepatic tissue ● Lecithin-cholesterol acyltransferase (LCAT) converts free cholesterol in cholesterol ester, which moves into center of HDL particle “Good” vs. “Bad” Cholesterol ● Cholesterol transported by LDL and HDL is the same Short Chain and Long Chain Fatty Acids Short-chain fatty acids: Fatty acids with fewer than 6 carbon atoms that are only produced by bacterial fermentation of polysaccharides that resist digestion in the small intestine (e.g. dietary plant matter) and can enter the colon Stimulates active Na+ and Cl- absorption to promotes water reabsorption by osmosis and therefore retain calories and electrolytes Can be used for energy by epithelial cells in the colon and the central nervous system (can pass through BBB) Can be absorbed through the portal vein into the blood E.g. Acetate, Propionate, and Butyrate Short-Chain and Long-Chain Fatty Acids Long-chain fatty acids Fatty acids with 14 or more carbons and are the building blocks of lipids or fats Found in most fats and oils and cannot cross the BBB Because they cannot be absorbed directly into the blood, they are reassembled into triglycerides and packaged into chylomicrons. The chylomicron is released into a lacteal, a lymphatic capillary within the small intestine, -> lymphatic system -> thoracic duct -> left subclavian vein (into blood) -> wherever they need to go Omega-3 and Omega -6 Fatty Acids (Essential Fatty Acids) The body needs minimal amounts of molecules for its own anabolic reactions (synthesis reactions) However, there are some molecules (e.g. essential fatty acids) that cannot be synthesized within the body and must be obtained through diet Omega-3 Fatty Acids: (n-3) Polyunsaturated fatty acids that have their first double bond on the 3rd carbon from the methyl end (-CH3) Alpha-linolenic acid (ALA): found in oily fish has 18 carbons, but it has three double bonds, with its first double bond on the 3rd carbon from the Omega-3 and Omega -6 Fatty Acids Omega-6 Fatty Acids: (n-6) Polyunsaturated fatty acid that has its first double bond on the sixth carbon from the methyl end. Linolenic acid: found in corn oil, contains 18 carbons with 2 double bonds, Mammals lack enzymes to insert this double bond at the n-6 or n-3 positions and must eat linolenic acid and alpha-linolenic acid Studies have suggested that omega-3 fatty acids offer protection against cardiovascular disease-- inhibit platelet function in thrombus formation and the Statins and HMG-coenzyme A reductase Statins are lipid-lowering drugs, also known as HMG-CoA reductase inhibitors People with dangerously high LDL cholesterol concentrations take these drugs Function: E.g. Lipitor Inhibits enzyme HMG-Coenzyme A reductase-HMG-coenzyme A reductase: integral protein of endoplasmic reticulum membranes that catalyzes the rate-limiting step in cholesterol synthesis (Mevalonate pathway), binds HMG-CoA Statins structurally similar to HMG-CoA and can compete for its active site Decreases the ability of the liver to produce its own cholesterol which stimulates production of LDL receptors which then Questions?