Fatty Acid Oxidation and Ketosis*this is the last portion of the section we didn’t finish for the last examRegulation of β-Oxidation• Enhanced by:o Fasting – because we need energy during fasting. Glucagon favored. CPT-1 is increased to facilitate β-Oxidationo Uncontrolled diabeteso Hormones which increase cAMP – glucagon and epinephrineo Endurance trainingo Epinephrine leads to an increase in lypolysis increase in β-Oxidation• Inhibited by:o Malonyl CoA High levels during fatty acid synthesis decrease in β-Oxidation Inhibits fat translocation into mitochondria (carnitine step)o Fed state – increase in insulin causes decrease in CPT-1o Disease that lead to carnitine deficiency and deficiencies of β-Oxidation enzymes can lead to hypoglycemiaKetone Body Formation• Made in the liver, used in extra hepatic tissues• Intermediate is HMG-CoA• Consists of 3 compounds Acetoacetate, β-hydroxybutyrate, Acetone• Occurs during conditions when fat oxidation is overly active which leads to an accumulation of Acetyl CoAo 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• β-Oxidation: Acetyl CoA enters TCA cycleo if β-Oxidation is increased, there is an increase in Acetyl CoAo 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 energyo 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 β-OxidationKetone Body Formation link with β-Oxidation both are being formed under the same conditions; increase in β-Oxidation leads to increase in Acetyl CoA leads to an increase in ketone body formationFunction of Ketone Bodies• Used for energy by extra hepatic tissues to conserve glucose (ex: muscle; brain during adapted starvation)o In extra hepatic tissues, ketone bodies are converted back into Acetyl CoA via the TCA cycle to produce energyo Therefore, ketone bodies can be used as energy source when CHO is low and helps to conserve blood glucosePrecautions 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 fatalLipid Metabolism in TissuesLipid 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 ATPo 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’sLipid Metabolism in the Adipose Tissue• Major function = storage of fat• Diets which promote fat synthesiso High energyo High carbohydrateo 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)• Triacylglycerol Synthesis (lipogenesis)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 kinaseo 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 + Glycerolo 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 downo 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 occurso 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 ChartHigh energy diet leads to increase in Glucose which leads to an increase in Insulin; promotes storage of fat and stimulates Glut 4Glucose then undergoes Glycolysis; Glucose-6-PO4 can undergo Glycolysis to form pyruvate or DHAP-Pyruvate Acetyl CoA- DHAP Glycerol-3-PO4OR, Glucose can enter HMP shunt to regenerate NADH (for fatty acid synthesis) to convert to Acyl CoAAcyl CoA (from HMP shunt) and Glycerol-3-PO4 (from DHAP) can esterify into triglyceridesTAG’s undergo hydrolysis (lipolysis by HSL) in Adipose Tissue; Glycerol + FA’s formedGlycerol enters circulationHSL (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 circulationThese 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,
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