Regulation of FA Oxidation and Ketone Bodies PDF

MEDICAL BIOCHEMISTRY REGULATION OF FA OXIDIZATION AND KETONE BODIES OBJECTIVES: STUDENT LEARNING OUTCOMES: OXIDIZATION OF FA AND KETONE BODIES DESCRIBE THE REGULATION OF ΒOXIDIZATION OF FA DESCRIBE THE SYNTHESIS AND OXIDIZATION OF KETONE BODIES DESCRIBE THE REGULATION OF KETONE BODY SYNTHESIS REGULA...

MEDICAL BIOCHEMISTRY REGULATION OF FA OXIDIZATION AND KETONE BODIES OBJECTIVES: STUDENT LEARNING OUTCOMES: OXIDIZATION OF FA AND KETONE BODIES DESCRIBE THE REGULATION OF ΒOXIDIZATION OF FA DESCRIBE THE SYNTHESIS AND OXIDIZATION OF KETONE BODIES DESCRIBE THE REGULATION OF KETONE BODY SYNTHESIS REGULATED BY INSULIN AND GLUCAGON LEVELS THAT CHANGE WITH GLUCOSE LEVELS INSULIN RELEASED DURING FED STATE (GLUCOSE HIGH) GLUCAGON LEVELS INCREASE DURING FASTING STATE (GLUCOSE LOW) REGULATION OF FA OXIDIZATION BASICALLY WHEN ENERGY IS NEEDED (FASTING) FAVORS FA ΒOXIDIZATION AND WHEN ENERGY IS NOT NEEDED (FED) FAVORS FA SYNTHESIS REGULATION OF Β-OXIDATION HORMONES RELEASED FROM FASTING, ENERGY DEMAND LEVELS ATP, NADH, COASH POOL IS AN AEROBIC PATH SINCE NEEDS TCA, ETC NOTE: Hormones control supply of FA from blood 3. ATP use NOTE: Carnitine palmitoyl transferase I is inhibited by malonyl-CoA REGULATION OF ΒOXIDATION COASH MITO POOL MITOCHONDRIA COA IS REQUIRED TO GENERATE FATTY ACYL-COA FROM FATTY ACYL CARNITINE REGULATION OF ΒOXIDATION 2. MALONYL COA FIRST INTERMEDIATE FORMED IN FA SYNTHESIS SYNTHESIS ON OXIDATION OFF REGULATION OF Β-OXIDATION REGULATION AT ATP/ADP RATIO RATE OF ATP USE CONTROLS RATE OF ETC AND REGULATES RECYCLING OF NAD+ AND FAD AS ELECTRON ACCEPTORS IN Β OXIDATION METABOLISM OF KETONE BODIES FATTY ACIDS ARE MAJOR FUEL DURING FASTING: LIVER FORMS KETONE BODIES SKELETAL MUSCLES CONVERT KETONE BODIES TO ACETYL COA COMPLETE OXIDATION TCA Fig. 17 SYNTHESIS OF KETONE BODIES: LIVER MITO MATRIX FROM ACETYL COA IN MATRIX THIOLASE (LAST REACTION OF FA OXIDATION) IS REVERSIBLE ACETOACETYL-COA ONLY MADE WHEN HAVE HIGH ACETYL-COA LEVELS Fig. 18 SYNTHESIS OF KETONE BODIES: LIVER MITO MATRIX SYNTHESIS OF KETONE BODIES: ANOTHER AC-COA ADDED BY HMG (3-HYDROXY-3-METHYLGLUTARYLCOA) COA SYNTHASE GENERATE HMG COA HMG-CO LYASE CATALYZES THE CLEAVAGE OF HMG-COA TO FORM ACETYL-COA AND ACETOACETATE Fig. 18 SYNTHESIS OF KETONE BODIES: LIVER MITO MATRIX ACETOACETATE CAN ENTER BLOOD DIRECTLY, OR, BE REDUCED TO Β-HYDROXYBUTYRATE WHICH THEN ENTERS THE BLOOD 3 DIFFERENT KETONES: NADH/NAD RATIO AFFECT RATIO ACETONE VOLATILE Under normal conditions the ratio of Acetoacetate to β-Hydroxybutyrate is 1:1 Alternate route Fig. 18 OXIDATION OF KETONE BODIES OXIDATION OF KETONE BODIES OCCURS IN MOST TISSUES (NOT LIVER OR RBC) KETONE BODIES TRANSPORTED IN BLOOD TO TISSUES, IN MITOCHONDRIAL MATRIX BOTH ACETOACETATE AND ΒHYDROXYBUTYRATE CAN BE OXIDIZED Β-HYDROXYBUTYRATE MUST BE OXIDIZED FIRST TO ACETOACETATE BY Β-HYDROXYBUTYRATE DEHYDROGENASE Fig. 19 OXIDATION OF KETONE BODIES GET NADH FROM 1ST REACTION CONVERTED BACK TO ACETYL COA REQUIRES ACTIVATION BY SUCCINYL COA (TCA CYCLE INTERMEDIATE) ENERGY YIELD ~ 2 ACETYL COAFig. 19 FATTY ACIDS, KETONES IN FUEL HOMEOSTASIS FATTY ACIDS ARE FUELS DURING FASTING, HIGH-FAT DIET. EXERCISE, STARVATION LIPOLYSIS STIMULATED BY ↓ INSULIN, ↑GLUCAGON, ↑EPINEPHRINE BRAIN USES KETONES SAVES GLUCOSE FOR RED BLOOD CELLS PREFERENTIAL USE OF KETONE BODIES PREFERENTIAL USE OF KETONE BODIES BY TISSUES: SKELETAL MUSCLE, HEART, LIVER USE FATTY ACIDS IN FASTING OR OTHER CONDITIONS INCREASING F.A. KETONE BODIES ARE USED BY: BRAIN CELLS INTESTINAL MUCOSA – TRANSPORT FATTY ACIDS TO BLOOD ADIPOCYTES – STORE FATTY ACIDS IN TAG FETUS – KETONE BODIES CROSS PLACENTA LIVER AND RED BLOOD CELL DO NOT OXIDIZE KETONE BODIES REGULATION KETONE BODY SYNTHESIS IN THE LIVER: 1. F.A. FROM ADIPOCYTES INCREASES 2. RELEASE INHIBITS MALONYL COA 3. Β-OXIDATION GIVES ATP NADH BUILDUP 4. OXALOACETATE -> MALATE IF NADH IS HIGH -> GLUCONEOGENESIS 5. ACETYL COA -> KETONE BODIES Ketogenesis Fig. 21 FATTY ACIDS ARE MAJOR FUELS, DURING FASTING REGULATION OF B-OXIDIZATION IS BY HORMONES, ATP AND FA SYNTHESIS LIVER CONVERTS F.A. TO KETONE BODIES KEY CONCEPTS THE KETONE BODIES – ACETONE, ACETOACETATE AND D-Β-HYDROXYBUTYRATE – ARE FORMED IN THE LIVE ACETOACETATE AND D-Β-HYDROXYBUTYRATE SERVE AS FUEL MOLECULES IN EXTRAHEPATIC TISSUES VIA OXIDATION TO ACETYL-COA AND ENTRY INTO TCA CYCLE OVERPRODUCTION OF KETONE BODIES IN UNCONTROLLED DIABETES CAN LEAD TO ACIDOSIS OR KETOSIS (SEVERE REDUCED CALORIE INTAKE CAN ALSO HAVE THIS EFFECT)