Fatty Acid Oxidation and Ketosis this is the last portion of the section we didn t finish for the last exam Regulation of Oxidation Enhanced by o Fasting because we need energy during fasting Glucagon favored CPT 1 is increased to facilitate Oxidation o Uncontrolled diabetes o Hormones which increase cAMP glucagon and epinephrine o Endurance training o Epinephrine leads to an increase in lypolysis increase in Oxidation Inhibited by o Malonyl CoA High levels during fatty acid synthesis decrease in Oxidation Inhibits fat translocation into mitochondria carnitine step o Fed state increase in insulin causes decrease in CPT 1 o Disease that lead to carnitine deficiency and deficiencies of Oxidation enzymes can lead to hypoglycemia Ketone Body Formation Made in the liver used in extra hepatic tissues Occurs during conditions when fat oxidation is overly active which leads to an accumulation of Intermediate is HMG CoA Consists of 3 compounds Acetoacetate hydroxybutyrate Acetone Acetyl CoA o Because Acetyl CoA is present in larger amounts than OAA Oxaloacetate the extra Acetyl CoA is used to produce ketones in the mitochondria of the liver Oxidation Acetyl CoA enters TCA cycle o if Oxidation is increased there is an increase in Acetyl CoA o When this happens we don t have enough OAA for Acetyl CoA to enter the TCA cycle remember Acetyl CoA OAA citrate is first step in TCA cycle because Acetyl CoA is accumulating o This leads to an increase in ketone bodies in the liver ketone bodies then enter circulation and are transported to tissues that need energy o This happens during starvation fasting severe prolonged exercise uncontrolled diabetes increase fatty diet low CHO Acetyl CoA is accumulating because OAA is a derivative of carbohydrates CHO so under these conditions there is low CHO availability so there is not enough OAA synthesized to match Acetyl CoA for Oxidation Ketone Body Formation link with Oxidation both are being formed under the same conditions increase in Oxidation leads to increase in Acetyl CoA leads to an increase in ketone body formation Function of Ketone Bodies starvation Used for energy by extra hepatic tissues to conserve glucose ex muscle brain during adapted o In extra hepatic tissues ketone bodies are converted back into Acetyl CoA via the TCA o Therefore ketone bodies can be used as energy source when CHO is low and helps to cycle to produce energy conserve blood glucose Precautions of Ketone Body Formation Ketone bodies are acidic when produced in excess over a long period of time uncontrolled diabetes they can lead to ketoacidosis Disruptions in acid base balance of the body can be fatal Lipid Metabolism in Tissues Lipid Metabolism in the Liver De novo synthesis of fatty acids fatty acid synthesis from non fat substances Glycerol 3 PO4 formed from o Glycerol via glycerol kinase phosphorylates Glycerol requires ATP o DHAP an intermediate in Glycolysis Glycerol 3 PO4 DHAP via Glycerol 3 PO4 dehydrogenase NADH used NADH H NAD Cholesterol synthesis Synthesis of VLDL s and HDL s Lipid Metabolism in the Adipose Tissue Major function storage of fat Diets which promote fat synthesis Triacylglycerol Synthesis lipogenesis o High energy o High carbohydrate o These promote fat synthesis because an increase in Glucose leads to an increase in Insulin Insulin favors storage of excess Glucose for fat synthesis Glucose precursor for fatty acid synthesis o Glycerol 3 PO4 must be formed from DHAP adipose tissue lacks glycerol kinase because it lacks glycerol kinase some of the glycerol will go into circulation and into the kidney lactating mammary gland etc because they have glycerol kinase o TAG synthesis increased by Insulin insulin enters tissues via Glut 4 glycolysis is occurring in tissue to produce DHAP Glycerol 3 PO4 The addition of 3 Fatty acyl CoA s to Glycerol 3 PO4 forms TAG s Hydrolysis of Triacylglycerol lipolysis into FA Glycerol o Catalyzed by Hormone Sensitive Lipase HSL Not catalyzed by LPL lipoprotein lipase anymore because lipoproteins have already delivered TAG s into tissue so now we need to break the TAG s down o HSL regulated covalently Stimulated by Catecholamines epinephrine norepinephrine glucagon adrenocorticotrophic hormone ACTH growth hormone GH cAMP is activated cAMP dependent protein kinase phosphorylates HSL activating it Methyl xanthines caffeine inhibits phosphodiesterase from inhibiting cAMP breakdown so cAMP cascade occurs o Phosphodiesterase breaks down cAMP and stops cAMP cascade HSL not phosphorylated inactive so methyl xanthines inhibit the enzyme Inhibited by Insulin Insulin will promote dephosphorylation of HSL by protein lipase stimulates protein lipase and phosphodiesterase Explanation of Chart High energy diet leads to increase in Glucose which leads to an increase in Insulin promotes storage of fat and stimulates Glut 4 Glucose then undergoes Glycolysis Glucose 6 PO4 can undergo Glycolysis to form pyruvate or DHAP Pyruvate Acetyl CoA DHAP Glycerol 3 PO4 OR Glucose can enter HMP shunt to regenerate NADH for fatty acid synthesis to convert to Acyl CoA Acyl CoA from HMP shunt and Glycerol 3 PO4 from DHAP can esterify into triglycerides TAG s undergo hydrolysis lipolysis by HSL in Adipose Tissue Glycerol FA s formed Glycerol enters circulation HSL active with PO4 inhibited by insulin stimulates phosphodiesterase breaks down cAMP and stimulates protein lipase cleaves phosphate Caffeine tea will also degrade phosphodiesterase The FA s made from hydrolysis are composed of 2 pools one that is being produced by lipolysis and one that is from the FA that went into circulation These FA pools can go back into adipose tissue from lipolysis or circulation to be broken into Acyl CoA Sometimes the rate of esterification formation of TAG s cannot keep up with the rate of lipolysis hydrolysis of TAG s into Glycerol FA s this leads to more FA s in blood circulation which will then be transported to the liver and undergo TAG synthesis leading to fatty liver this happens in cases of uncontrolled diabetes excessive alcohol intake etc To oxidize alcohol NADH is necessary NADH gets depleted if excess alcohol is consumed leading to fatty liver and sclerosis Phospholipid and Triacylglycerol Synthesis Formation of Glycerol 3 PO4 From Glycerol via glycerol kinase in liver only remember not in adipose tissue or muscle because kinase isn t present or has very low activity From DHAP in liver adipose tissue Formation of Phosphatidic Acid a common intermediate in
View Full Document
Unlocking...