Lipid Degradation Fatty Acids Lecture

Lipid Degradation 4 Lipid Degradation: Fatty Acids Fat Catabolism Glycogenolysis Glycolysis Pyruvate Oxidation Krebs' Cycle Phosphorylation Oxidative Fatty Acid Degradation • Fat as a fuel; ingestion of the “chunks” • How fats are mobilized and transported in animal tissues • COMPARTMENTATION o How fats are oxidized in mitochondria – – – – Glycerol Saturated Fatty Acids Un-saturated Fatty Acids Odd-chain Fatty Acids o Blocks to oxidation in mitochondria: How “ketone bodies” are utilized o Fatty-acid metabolism in other organelles 5 Fatty Acid Degradation Dietary Fatty Acids Are Absorbed in the Vertebrate Small Intestine • Used by muscle, liver, heart • Stored by adipose Fatty Acid Degradation Chylomicrons Phospholipids 6 Fatty Acid Degradation • Fatty Acid Oxidation is a Major Energy Source • About one-third of human energy needs comes from dietary triacylglycerols (fat). • There are differences in tissue utilization. About 80% of energy needs of mammalian heart and liver are met by oxidation of fatty acids. There are FOUR stages in the • Many hibernating animals, such as catabolism of lipids: 1) Mobilization from tissues grizzly bears, rely almost exclusively (mostly adipose) on fats as their source of energy. 2) Activation of fatty acids 3) Transport 4) Oxidation Fatty Acid Degradation • Fuel Storage of Fat is efficient • The advantage of fats over polysaccharides: – Fatty acids carry more energy per carbon because they are more reduced. – Fatty acids complex or carry less water because they are nonpolar. • Glucose and glycogen are for short-term energy needs and quick delivery. • Fats are for long-term (months) energy needs, storage, and have slow delivery. • How are fat stores accessed? Fatty acids come in all types: ± double bonds, long & short, odd & even, etc. 7 Fatty Acid Degradation Mobilization • Stored Triacylglycerides are released in response to Hormone signals • Hormones trigger a mobilization “cascade” that activates lipases • Lipases are activated by hormones glucagon and epinephrine. ❶ ❷❸❹ • In the case of glucagon, Protein Kinase A (PKA) is activated, ❺❼ which leads to the progressive activation of 3 lipases, one for each position on glycerol. ❸❻❽ • Fats are degraded into fatty acids and glycerol in the cytoplasm of adipocytes. ❽❾ • Fatty acids are transported to other tissues through the blood. Fatty Acid Degradation •Glycerol is a sugar alcohol and is converted to a glycolytic intermediate •Glycerol kinase activates glycerol at the expense of ATP. •Subsequent reactions recover more than enough ATP to cover this cost. •Allows limited anaerobic catabolism of fats •A redox reaction is required to convert the alcohol to a ketone. Done by glycerol-3-phosphate dehydrogenase •We’ll see this reaction again in lipid synthesis 8 Fatty Acid Degradation •Glycerol is a sugar alcohol and is converted to a glycolytic intermediate •Glycerol kinase activates glycerol at the expense of ATP. •Subsequent reactions recover more than enough ATP to cover this cost. •Allows limited anaerobic catabolism of fats •A redox reaction is required to convert the alcohol to a ketone. Done by glycerol-3-phosphate dehydrogenase •We’ll see this reaction again in lipid synthesis Fatty Acid Degradation Activation • Like the activation of sugars by phosphorylation, fatty acids must also be activated. • Not having any alcohol groups, esterification of the carboxylate is the only chemistry available. • A thio-ester is a higher energy bond than a simple ester: use Coenzyme A. • Conversion to Fatty Acyl-CoA targets these molecules for oxidation Fatty acyl–CoA synthetase 9 Fatty Acid Degradation Activation • Like the activation of sugars by phosphorylation, fatty acids must also be activated. • Not having any alcohol groups, esterification of the carboxylate is the only chemistry available. • A thio-ester is a higher energy bond than a simple ester: use Coenzyme A. • Conversion to Fatty Acyl-CoA targets these molecules for oxidation Fatty acyl–CoA synthetase If we are doing catabolism, we have to get Fatty-acyl CoA into the mitochondria. Fatty Acid Degradation Transport COMPARTMENTATION: Mitochondria Acyl-Carnitine/Carnitine Transport • b oxidation of fatty acids occurs in mitochondria. • Fatty acyl-CoAs are transported via acyl-carnitine/carnitine transporter. 10 Fatty Acid Degradation Acyl-Carnitine/Carnitine Transport Carnitine uptake transporter Fatty acyl-CoA Synthetase Transport • Small (< 12 carbons) free fatty acids diffuse freely across membranes. • Larger fatty acids are transported via fatty acid transporters on the plasma membrane. Carnitine acyltransferase 1 Carnitine acyltransferase 2 • Fatty-acyl-CoA Synthetase is attached to the OUTER mitochondrial membrane. Carnitine/acylcarnitine • transporter Recent evidence shows that its associated with an integral membrane transporter: Fatty-acyl Transporter Protein I • Together, they are indicated on the figure as AS. 11