fatty acid transport, metabolism

fatty acid transport, metabolism - Bioc 460 Spring 2010...

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Unformatted text preview: Bioc 460 Spring 2010 Lectures 34 Lipid Metabolism I Dr. Lisa Rezende How are lipids transported in the blood stream? How are lipids oxidized and stored? How does lipid metabolism fit into the larger picture of metabolism? What happens when lipid metabolism is disrupted by disease state or drugs? Learning objec-ves: Fa2y acid transport and oxida-on Discuss the biological raJonale for the following: packaging of triacylglycerols in lipoprotein parJcles, binding of circulaJng faNy acids by albumin, and binding of intracellular faNy acids by faNy acid binding proteins. Describe how faNy acid oxidaJon can be controlled by the acJviJes of pancreaJc lipase and hormone sensiJve lipase. Write the balanced equaJon for the oxidaJon of palmitate (C18). Calculate the ATP yield for the complete oxidaJon of a faNy acid of a given size. Compare and contrast the amount of energy produced per carbon from complete oxidaJon of faNy acids and glucose. Explain how faNy acid oxidaJon can be used as a source of water. Describe the different metabolic fates for acetyl CoA produced in faNy acid oxidaJon. IdenJfy where and when ketone body synthesis and ketone body oxidaJon occurs. Define ketoacidosis and explain how and when it occurs. Reading: Chapter 22 Sec-ons 22.1, 22.2, 22.3, and 22.4 Problems: 1, 9, 17 (a and b) and problem set. Lipid Metabolism Lipid Metabolism Lipids can be obtained from the diet or stored Dietary fats Stored Lipids (A\er much metabolism) Acetyl CoA Diges-on and transport of dietary lipids PancreaJc lipase Inhibitor = diet drug Metabolism of dietary fats and cholesterol Lipids travel the blood stream bound to apolipoproteins, forming parJcles that are classified based on density. Internal triglyceride stores are mobilized in response to glucagon or epinephrine. Hormone-sensiJve lipase is phosphorylated and acJvated by PKA. FaNy acids released by lipase is exported and bound to serum albumin in circulaJon. FaNy acid dissociates from albumin in areas with low free faNy acid. Free faNy acid is transported across membrane by faNy acid transporters. Lipids mobilized from adipose Jssue must also be transported Image courtesy of TS Tsao Once inside the cell, the first step in faNy acid uJlizaJon is acylaJon with coenzyme A to form faNy acyl-CoA. Balanced equa-on (where R denotes fa2y acyl tail): RCOO- + CoA + ATP + H2O -> RCO-CoA + AMP + 2 Pi + 2 H+ Note the reacJon requires hydrolysis of ATP and pyrophosphate (ATP-> AMP + 2Pi). What affect with this step have on the net ATP yield for faNy acid oxidaJon? FaNy acyl-CoA is transported into mitonchondrial matrix through the carniJne acyltransferase I and II. (CarniJne acyltransferase I & II are also known as carniJne palmitoyltransferase I & II (CPT-I & II)) Note regula-on by compartmentaliza-on: Cytosolic and mitochondrial coenzyme A pools are kept separately with different concentraJons. CoA plays a major role in the synthesis of fat, which takes place in cytoplasm. The products of -oxidaJon are acetyl- CoAs for even-chain faNy acids*, which are then fed into citrate acid cycle for further oxidaJon. Therefore oxidaJon of a saturated even-chain fa2y acid will yield 1 molecule of acetyl CoA for every 2 carbons in the faNy acyl tail. For palmitate (C16 shown right) the balanced equaJon for the complete oxidaJon is: Palmitate + 7 NAD+ + 7 FAD + 8 CoA + 7 H2O + ATP 8 acetyl CoA + 7 NADH + 7 FADH2 + AMP + 2 Pi + 7 H+ *Odd chain and/or unsaturated faNy acyl chains require further metabolism that is not covered in this course oxida-on proceeds through cycles of four enzyme-catalyzed reacJons: an oxidaJon, a hydraJon, a second oxidaJon, and thiolysis. Feed into Electron transport system During the two oxidaJon steps pairs of electrons are transferred to NAD+ and FAD. Each cycle produces one molecule of acetyl CoA. Feeds into the citrate cycle Cycle repeats -oxida-on reac-ons for palmitate (C16) Palmitoyl-CoA + 7 CoA + 7 FAD + 7 NAD+ + 7 H2O --> 8 acetyl CoA + 7 FADH2 + 7 NADH + 7 H+ Courtesy of Dr. RL Miesfeld ATP currency exchange ra/os ____NADH from b-oxidaJon ( x ~2.5 ATP) = ATP ____ FADH2 from b-oxidaJon ( x ~1.5 ATP) = ATP ____NADH from citrate cycle ( x ~2.5 ATP) = ATP ____ FADH2 from citrate cycle ( x ~1.5 ATP) = ATP For a grand total = ATP A"er subtrac,ng the ___ ATP required for fa8y acyl CoA ac,va,on (remember AMP --> PPi) And adding the ___ ATP obtained from eight turns of the citrate cycle; Courtesy of Dr. RL Miesfeld The total payout for the complete oxida-on of palmitate is ____ ATP Comparison of energy density between fa2y acid and glucose Compare this to the calculaJon we did on the previous slide: Respiratory QuoJent Fuel Palmitate (x3) Glucose (x8) ATP formed 324 256 O Atoms used 138 96 ATP formed / carbon atom 6.75 5.33 CO2 formed / O2 used 0.7 (48/69) 1.0 (48/48) Why are faNy acids more energy dense than carbohydrates? Added Benefit: Lipid oxidaJon through electron transport chain produces water. 2 NADH + 2 H+ + O2 2 H2O 2 FADH2 + O2 2 H2O Bears nearly double their body weight in preparing for hibernaJon- can you now explain How this "faNening up" supplies energy, heat, and water during hibernaJon? How does fa2y acid oxida-on fit into the big picture? In a fasJng liver, increased levels of acetyl-CoA during oxidaJon of long- chain faNy acids "spares" glucose for gluconeogenesis (Randle effect). In skeletal muscle and heart, acJvaJon of pyruvate carboxylase by acetyl-CoA serves to increase flux in TCA cycle. Does not operate in muscle or heart -oxida-on -oxida-on Liver only Muscle heart Why is flux through citrate cycle increased in when pyruvate carboxylase is acJve in the absence of gluconeogenesis? In mammals, fa2y acids are oxidized in the peroxisome. Inborn errors of metabolism associated with Defects in faNy acid oxidaJon in the peroxisome X-linked adrenoleukodystrophy: Impaired transport of very long chain faNy acids into peroxisomes. Zellweger syndrome: A disease of peroxisome biogenesis. In many paJents it is caused by inherited mutaJons in membrane receptors that are required for imporJng proteins (like peroxisomal enzymes) into the peroxisome. Infants die within a year of life. Both diseases associated with increased very long (C26 or greater) chain faNy acids in the blood resulJng In vision and behavioral disorders. PaJents rarely survive into adulthood. Quick review: If you are a plant, you can convert faNy acids to glucose via The glyoxalate pathway -> Remember, if you are a mammal fa2y acids cannot be to glucose. What happens then when you have lots of fat for use, but not enough glucose? Focus on the metaboic flux not the steps in the pathway! While faNy acids cannot be converted to glucose, the glycerol moiJes of 2 triacylglycerols provide the backbone for 1 glucose molecule. What pathway can be used to convert glycerol to glucose? Ketogenesis Acetyl-CoA derived from faNy acid oxidaJon enters the citrate cycle only if carbohydrate metabolism is properly balanced. When faNy acid oxidaJon produces more acetyl-CoA than can be combined with OAA to form citrate, then the "extra" acetyl-CoA is converted to ketone bodies, including acetone. Ketogenesis (synthesis of ketone bodies) takes place primarily in the liver. Explain why the citrate cycle can be "overwhelmed" by too much acetyl Co A. Courtesy of Dr. RL Miesfeld Under fasJng condiJon, withdrawal of TCA cycle intermediates for gluconeogenesis facilitates ketone body formaJon. "Sweet" smell of diabeJc paJents' breath Lactate Pyruvate CO2 CO2 Metabolism of Ketone Bodies Ketone bodies synthesized in the liver are uJlized by heart, skeletal muscle, and brain for energy during fasted state. Heart and skeletal muscle will uJlize whatever substrates they can get, while brain avoids fat oxidaJon. Can be metabolized In the citrate cycle in brain and muscle! Note the same physiological state (high fat, low glucose) triggers different pathways in different cell types. Ketoacidosis: drop in blood pH caused by excessive blood ketone body concentraJon. It is usually associated with diabetes. Insulin deficiency Uncontrolled lipolysis in adipose Jssue (InacJvaJon of acyltransferase and acJvaJon of hormone-sensiJve lipase) Release of free faNy acids into blood Increased FFA delivery to liver Increased -oxidaJon in liver Courtesy of Dr. Tischler pKa 4.7 Increased ketone body formaJon in liver pKa 3.6 Ketogenic diet (high fat/low carbohydrate, Atkins diet is a modified ketogenic diet) is followed by many bodybuilders. More importantly, it has been shown to be an effecJve treatment for epilepsy (link to Epilepsy FoundaJon). ...
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