Cholesterol & Fatty Acid Metabolism - Kevin Ahern's BB 451 Lecture #37 2017
1. Contact - [email protected] 2. Kevin's lectures with The Great Courses - https://www.thegreatcoursesplus.com/b... 3. Kevin's Lecturio videos for medical students - https://www.lecturio.com/medical-cour... 4. Course materials at https://kevingahern.com/biochemistry-... 5. Course video channel at • Citric Acid Cycle I - Kevin Ahern's BB 451... 1. Cholesterol in the body is either there as a result of 1) synthesis; 2) diet; or 3) storage/recycling. 2. In the digestive system, bile acids and mechanical agitation of the stomach help emulsify fats. 3. In intestines, hydrolysis of fatty acids from fats by lipases, yield soapy like substances that help emulsify lipids for transport across the intestinal wall. 4. After movement across the intestine, lipids are packaged in chylomicrons. They move through the lymph system into capillaries where they get stuck. 5. Action of lipoprotein lipase in the capillaries removes some of the fat from the chylomicrons and they shrink in size and exit the capillaries and move to the liver. 6. The liver senses the body's need for lipids via LDL receptors. If lipids are needed, VLDLs are packaged by the liver and released. These get degraded by lipases and other enzymes to IDLs and LDLs. If the liver LDL receptor cannot detect LDLs in the blood, it continues to release more lipoprotein complexes. 7. Defects in liver LDL receptors are a leading cause of high blood cholesterol. 8. LDLs are associated with formation of atherosclerotic plaques. These form as a result of free radicals which oxidize unsaturated fatty acids in LDLs. Macrophages may attack these and form the basis of atherosclerotic plaques. 9. LDLs have the highest concentration of cholesterol of any of the complexes, delivering cholesterol into cells by receptor-mediated endocytosis. 10. HDLs are associated with reducing levels of cholesterol. HDLs are reduced in smokers, but are increased in response to exercise. 11. If a person has high cholesterol, the first approach is to see if levels can be brought down by dietary changes. If they cannot, then drugs are used to stop 1) endogenous synthesis and/or 2) recycling. 12. Endogenous synthesis drugs (statins) target HMG-CoA Reductase. Highlights - Fatty Acid Oxidation 1. Fats are broken down by enzymes known as lipases. Hormone sensitive triacylglycerol lipase is the only regulated enzyme of fat or fatty acid breakdown. 2. Triacylglycerol lipase cleaves the first fatty acid off of a fat. 3. Glycerol, is the only part of a fat that can be made into glucose. Fatty acids travel in the bloodstream carried by serum albumin. 4. Fatty acid oxidation occurs in the mitochondrial matrix. In the cell, fatty acids are attached to CoA and at the mitochondrion, the CoA is replaced by carnitine. Inside the mitochondrial matrix, the carnitine is replaced by CoA again. 5. Steps in fatty acid oxidation include dehydrogenation, hydration, oxidation, and thiolytic cleavage. The dehydrogenation and oxidation reactions yield reduced electron carriers (FADH2 and NADH). The double bond formed in the first dehydrogenation reaction is in the trans form. Thiolytic cleavage is catalyzed by the enzyme called thiolase. 6. The first reaction of fatty acid oxidation involves a set of enzymes know as acyl dehydrogenases. These are specific for fatty acids with long, medium, or short chains. The medium chain acyl dehydrogenase has been implicated in some instances of sudden infant death syndrome. 7. The long chain acyl dehydrogenases are found in peroxisomes and this is where oxidation of long chain fatty acids (longer than 20 carbons) begins (not in the mitochondrial matrix). Oxidation here involves transfer of electrons to oxygen to make hydrogen peroxide, instead of FADH2. Peroxisomal fatty acid oxidation is therefore LESS efficient than mitochondrial beta oxidation. 8. Acyl dehydrogenases that work on medium chain (8-20 carbons) and short chain (less than 8 carbons) fatty acids are found in the mitochondrial matrix. The enzyme working on medium chain fatty acids has been linked to sudden infant death syndrome, when deficient. 9. The first step of oxidation generates a trans-intermediate plus FADH2. The second step involves addition of water across the trans double bond to create an intermediate in with an OH on carbon 3 in the L configuration. The third step involves oxidation of the hydroxyl intermediate to a ketone on carbon 3. The last step involves cleaving off of an acetyl-CoA and production of a fatty acyl-CoA with two fewer carbons. The last step is catalyzed by the enzyme thiolase. 10. The reactions of beta oxidation up to the thiolase reaction chemically mirror the reactions of the oxidation of succinate up to oxaloacetate. 11. Seven cycles of beta oxidation of palmitoyl-CoA in the matrix yield 8 acetyl-CoAs.
