L23 - Metabolism of Free Fatty Acids PDF

23 Metabolism of free fatty acids ILOs By the end of this lecture, students will be able to 1. 2. 3. 4. 5. Outline process and regulators of fatty acid synthesis Deduce interplay between lipogenesis and lipolysis Differentiate types of FA oxidation Appraise the role of beta oxidation of fatty acid i...

23 Metabolism of free fatty acids ILOs By the end of this lecture, students will be able to 1. 2. 3. 4. 5. Outline process and regulators of fatty acid synthesis Deduce interplay between lipogenesis and lipolysis Differentiate types of FA oxidation Appraise the role of beta oxidation of fatty acid in energy production Discuss the regulation of FA oxidation Fatty acid release from fat  As you recall, fatty acids are stored in white adipose tissue, combined with glycerol, in the form of neutral Triacylglycerol (TAGs), and they serve as the body’s major fuel storage reserve. The yield from the complete oxidation of fatty acids to CO2 and H2O is 9 kcal/g fat (as compared to 4 kcal/g protein or carbohydrate).  The mobilization of stored fat requires the hydrolytic release of FFA and glycerol from their TAG form. This process of lipolysis is achieved by lipases. It is initiated by adipose triglyceride lipase (ATGL), which generates a diacylglycerol that is the preferred substrate for hormone sensitive lipase (HSL). The monoacylglycerol (MAG) product of HSL is acted upon by MAG lipase.The process of lipolysis is activated by catecholamines and glycolysis and inhibited by insulin. (Refer to tissue organization block, metabolism of adipose tissue)  End products of lipolysis include glycerol and free fatty acids which are both used for production of energy. Fate of released free fatty acids:  The FFA move through the cell membrane of the adipocyte to the blood, where they bind to serum albumin. They are transported to tissues such as muscle, enter cells, get activated to their CoA derivatives (acyl CoA), and are oxidized for energy in mitochondria.  Regardless of their levels, plasma FFA cannot be used for fuel by red blood cells (RBC), which have no mitochondria.  The brain does not use fatty acids for energy to any appreciable extent, but the reasons are less clear.  Note: Over 50% of the fatty acids released from adipose TAG are reesterified to glycerol 3phosphate. WAT does not express glycerol kinase Page 1 of 5 Fatty acid β-oxidation (Figure 1) The major pathway for catabolism of fatty acids is a mitochondrial pathway called β-oxidation, in which two-carbon fragments are successively removed from the carboxyl end of the fatty acyl CoA, producing acetyl CoA, NADH, and FADH2.It occurs for even numbered saturated f.a. Conditions in which the rate of beta oxidation is increased: Any condition in which glucose can’t be used as the primary source of energy, such as prolonged fasting with depletion of glycogen stores, starvation, diabetes mellitus and ketogenic diets. For beta oxidation to occur, the following steps must occur: 1. Activation of fatty acid(conversion to acyl CoA) After a FA enters a cell, it is converted in the cytosol to its active form CoA derivative by fatty acyl CoA synthetase (thiokinase), an enzyme of the outer mitochondrial membrane. This is accompanied by conversion of ATP to AMP (i.e. consuming 2 high energy bonds) Figure 1: Steps of beta oxidation of even numbered saturated fatty acids 2. Translocation:  Because β-oxidation occurs in the mitochondrial matrix, the fatty acid must be transported across the inner mitochondrial membrane that is impermeable to CoA. Short and medium chains fatty acids (20 carbons) fatty acids branched-chain fatty acids (e.g., phytanic acid in the diet) are metabolized by a-oxidation, which releases a terminal carboxyl as CO2 one at a time. This occurs mainly in brain and nervous tissue. V)Omega (ω) oxidation of Fatty Acids Oxidation at the terminal carbon (ω -carbon) can be carried out by enzymes in the endoplasmic reticulum, creating a dicarboxylic acid. This process requires cytochrome p450, NADPH, and molecular O2. Normal b-oxidation can then occur at both ends of the fatty acid. Page 5 of 5