Lipid Metabolism & Fatty Acid Oxidation Lecture Notes PDF

Lipid metabolism Lipolysis & B-oxidation of fatty acids  Lipolysis The hydrolytic release of three fatty acids and glycerol from their TAG form. (mobilization of stored fat). Requirements for TAG mobilization:  Lipolysis is carried out by three enzymes present in adipose tissue :...

Lipid metabolism Lipolysis & B-oxidation of fatty acids  Lipolysis The hydrolytic release of three fatty acids and glycerol from their TAG form. (mobilization of stored fat). Requirements for TAG mobilization:  Lipolysis is carried out by three enzymes present in adipose tissue : 1. Triacylglycerol lipase 2. Hormone sensitive diacylglycreol lipase (HSL). 3. Monoacylglycerol lipase Steps of Lipolysis  Regulation of lipolysis 3',5'-Cyclic AMP is produced in the adipocyte when one of several hormones (such as epinephrine or glucagon) binds to receptors on the cell membrane, and activates adenylyl cyclase Lipase enzyme is activated when phosphorylated by a 3 ',5 '-cyclic AMP(cAMP)– dependent protein kinase.  Adrenaline and glucagon Insulin Adenyl cyclase phosphodiastrase + ATP → cAMP → AMP ↓ Insulin Phosphodiastrase - active PK ↓ Caffeine and active HSL theophylline Inactive ↓ Lipolysis  Lipolytic factors and Antilipolytic factors: Lipolytic hormone Antilipolytic factors: 1- Epinephrine and norepinephrine. 1- Insulin 2- Glucagon. 3- ACTH., 4- TSH. 2- Nicotinic acid (inhibit adenylyl 5- Growth hormone. cyclase)  (caffeine): (inhibits phosphodiastrase)  Sympathetic nervous system 3- Prostaglandins Causes of excessive lipolysis: where there is a need for energy : (Insulin is low) 1. Starvation. 2. Diabetes mellitus. 3. Low carbohydrate diet. 4. In certain infectious disease as in tuberculosis ( due to high catabolic state). Regulation of lipolysis and lipogenesis  Fatty acid oxidation Among the different foodstuffs, lipids give the maximum amount of energy, 3 different pathways for fatty acids oxidation are present α, β, ω.  Fatty acid oxidation Fatty acid oxidation occurs by removal of 2-C units at a time with oxidation at the b-carbon of the fatty acid in the form of acetyl CoA     CH3 CH2 CH2 CH2 CH2 COOH Beta Oxidation Cleavage of fatty acids to acetate in tissues Occurs in mitochondria [O] [O] [O] [O] [O] [O] [O] [O] CO2H 9 CH3COSCoA  Complete Oxidation Steps in Beta Oxidation Fatty Acids: 9 kcal/g Carbohydrates: 4 kcal/g Protein: 4 kcal/g  Fatty Acid Activation by Esterification with CoASH (in the cytoplasm).  Membrane Transport of Fatty Acyl CoA Esters (across mitochondrial membrane)  Carbon Backbone Reaction Sequence  Dehydrogenation  Hydration  Dehydrogenation  Carbon-Carbon Cleavage (Thiolase Reaction)  β-oxidation of fatty acids  Fatty Acid β-Oxidation needs: 1. Activation of Fatty acid into acyl CoA 2. Translocation to mitochondria 3. β-oxidation  It is a mitochondrial pathway in which two-carbon fragments (acetyl CoA) are removed from the carboxyl end of the fatty acyl CoA  Organ location:  liver, kidney, heart and skeletal muscle.  It doesn’t occur in erythrocytes due to absence of mitochondria.  It doesn’t occur in brain because of impermeable blood brain barrier.  Transport of fatty acids into mitochondria. After the fatty acid is taken up by the cell, it is converted to acyl CoA in the cytosol by fatty acyl CoA synthase (thio-kinase). O Carnitine Shuttle: Carnitine-mediated transfer of the fatty acyl moiety into the mitochondrial matrix is a 3-step process.  Carnitine shuttle net effect is transport of long-chain acyl CoA from outside to the inside of mitochondria Thiokinase  Carnitine structure What is carnitine? B-hydroxy γ-trimethyl ammonium butyric acid Sources of carnitine: Carnitine can be obtained from the diet, where it is found primarily in meat products. Synthesized from the amino acid lysine and methionine in the liver and kidney but not in skeletal or heart muscle. Plant-based foods rich in the amino acids lysine and methionine helps the body to produce adequate amounts of carnitine. Vegan sources of Foods rich in Carnitine: Lentils, Beans and Quinoa. Tofu, Soy milk and Tempeh. (Tempeh or tempe is a traditional Indonesian food made from fermented soybeans). Pistachios and Pumpkin seeds.  Carnitine Acylcarnitine translocase Carnitine Acyltransferase II Carnitine Acyltransferase I 1. Carnitine acyl transferase I: catalyzes transfer of a fatty acid from acyl CoA to carnitine to form acyl carnitine. 2. Carnitine Acylcarnitine translocase: mediates transmembrane exchange of fatty acyl-carnitine for carnitine. 3. Carnitine acyl transferase II: catalyzes transfer of the fatty acid from acyl-carnitine to coenzyme A. So, the acyl carnitine is reconverted to acyl-CoA and free carnitine in the mitochondrial matrix  α-β unsaturated acyl CoA Β-hydroxy acyl CoA Β- keto acyl CoA Β- oxidation  Energy production of β-oxidation If palmitic acid (16 C), Net energy gain will be: (28 ATP+ 80 ATP) – 2 ATP =  108 ATP – 2 ATP = 106 .AT Calculation formula of energy production for fatty acid oxidation: (N/2 – 1) X 4 ATP) + (N/2 X 10 ATP) – 2) N represents number of carbon atoms of fatty acid. This fatty acid needs 7 cycles of oxidation reactions. Myristic acid, a How many oxidation cycles does myristic acid need? common saturated fatty acid with the molecular formula CH3(CH2)12COOH.  Regulation of fatty acid oxidation 1- Through energy production i.e. ↑ATP → ↓respiratory chain → ↓ β-oxidation. 2- Malonyl CoA inhibit CPT1(indirect).  Importance of β-oxidation. 1. Energy production. 2. Production of acetyl CoA which enter in many pathways. 3. Ketone body formation : Acetoacetyl CoA is the last 4 carbon atoms in the course of β-oxidation it may be converted into acetoacetate; one of ketone bodies.  Carinitine deficiency  - Deficiencies in carnitine lead to an inability to transport fatty acids into the mitochondria for oxidation.  Genetic CPT- deficiency affects the liver, heart and skeletal muscles  - This can occur in newborns and particularly pre-term infants.  Carnitine deficiencies also are found in patients undergoing hemodialysis, liver disease, malnutrition, vegetarian diets; increased requirement for carnitine: pregnancy, severe infections, burns, or trauma.  Symptoms: fasting hypoglycemia, mild occasional muscle cramping to severe weakness or even death.  Oxidation of odd number fatty acids  They are oxidized by the same steps of β-oxidation as that of fatty acids with even number, until the final three carbons are reached. Propanoic acid C3:0 CH3CH2COOH  This compound, propionyl CoA is metabolized by three step pathway:  Sources and Fate of succinyl CoA  Sources  Fate (Succinyl CoA functions)  Glucose formation  Oxidation of odd number fatty acid.  Heme synthesis.  Citric acid cycle.  Oxidation in citric acid cycle.  Catabolism of some amino  Activation of ketone bodies. acids e.g. leucine, valine and methionine.  Detoxification.  α-oxidation of fatty acids  The branched fatty acid as phytanic acid, is not a substrate for β-oxidation due to presence of methyl group on its β- position.  α-oxidation occurs mainly in brain and nervous tissues.  In α-oxidation there is one carbon atom removed at a time from α-position. It doesn’t require CoASH and doesn’t generate high energy phosphate  (Phytanic acid is 3, 7, 11, 15 tetramethyl palmitic acid, present in plants. Steps of α-oxidation Refsum’s disease: it is an autosomal recessive disorder due to disorder of α-oxidation. This leads to accumulation of phytanic acid in nervous tissue and produce nervous damage e.g. blindness and deafness  Differences between alpha and beta oxidation Beta oxidation Alpha oxidation Occurs in liver Occurs in brain Needs activation Doesn't need activation Gives energy Doesn't Give energy There is loss of 2 C per cycle There is loss of 1 C per cycle Needs CoA-SH Doesn't need