Nutrition and Metabolism Unit 1 Exam Study Guide: Regulation of Carbohydrates and Lipids
Nutrition and Metabolism Unit 1 Exam Study Guide: Regulation of Carbohydrates and Lipids NUTR 4550
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This 16 page Study Guide was uploaded by Victoria Hills on Tuesday February 2, 2016. The Study Guide belongs to NUTR 4550 at Clemson University taught by Dr. Elliot Jesch in Spring 2016. Since its upload, it has received 94 views. For similar materials see Nutrition and Metabolism in Nutrition and Food Sciences at Clemson University.
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Date Created: 02/02/16
Clemson University Spring 2016 Nutrition and Metabolism (NUTR 4550) Unit 1 Regulation Exam Study Guide I. Glycolysis • Figure 12.8 is showing glycolysis on the left side and gluconeogenesis on the right side + their corresponding regulatory factors • First regulated step in glycolysis: -‐ Glucose à Glucose-‐6-‐Phosphate via glucokinase/hexokinase -‐ Points of regulation: a) Insulin: o Up regulates glucokinase/hexokinase o Increases the concentration (number) of glucokinases/hexokinases in order for glucose to be phosphorylated to be glucose-‐6-‐phosphate o When carbohydrates (Such as glucose or fructose) are more quickly phosphorylated, more uptake of the carbohydrates is able to enter the cell b) Fructose-‐1-‐Phosphate: o Up regulates glucokinase/hexokinase via increasing its activity o Fructose-‐1-‐phosphate comes from fructose and is one of the pathways that fructose is able to enter glycolysis c) Fructose-‐6-‐Phosphate: o Down regulates (Inhibits) glucokinase/hexokinase when large amounts of fructose-‐6-‐phosphate are present from the step where glucose-‐6-‐phosphate à fructose-‐6-‐phosphate o Down regulates glucokinase/hexokinase in preparation rd for the next (3 ) step in glycolysis where fructose-‐6-‐ phosphate à fructose-‐1,6-‐bisphosphate via P6FK1 because fructose-‐6-‐phosphate is acting at this point as a precursor to this reaction (fructose-‐6-‐phosphate à fructose-‐1,6-‐bisphosphate) for regulation in order not to overwhelm the rest of glycolysis (This is known as feed back regulation) o Feed back regulation: Where a product of a reaction will feed back to the previous reaction à Here: A lot of fructose-‐6-‐phosphate will down regulate glucokinase/hexokinase activity • Second regulated step in glycolysis: -‐ Fructose-‐6-‐Phosphate à Fructose-‐1,6-‐Bisphosphate via P6FK1 (Phosphofructokinase) -‐ Points of regulation: a) ATP: o Down regulates PFK o Down regulates PFK because the cell has enough ATP so it is unnecessary to continue shuttling glucose/other monosaccharides in to produce more ATP o Key to note that ATP will not shut down this pathway but instead the monosaccharides will continue to go through glycolysis à Pyruvate à Acetyl CoA in order to enter fatty acid synthesis instead of continuing through the TCA cycle and electron transport chain o In general, ATP production is slowed down by heavy ATP presence in the cell b) Hydrogen (Protons): o Down regulates glucokinase/hexokinase o The protons are being referred to their place in the electron transport chain when they are being pumped into the inner mitochondrial space that creates the chemiosmotic gradient used to make ATP with ATP synthase o If the concentration of protons is sustained though, this means that the cell is signaling that there are enough reducing equivalents providing the protons so that the TCA cycle and glycolysis should slow down as a result c) AMP/Pi (Inorganic phosphate): o Up regulate PFK o When there is increased AMP and Pi present in the cell, the cell is sensing that it is currently using energy (ATP) o Therefore, it is necessary to continue having more of a flow of glucose into the cell through the glycolytic pathway d) Citrate (Indirectly): o Down regulates (slows down) PFK o Citrate is a TCA cycle intermediate that is formed when oxaloacetate and acetyl CoA are combined o As citrate circles back around to oxaloacetate in the full TCA cycle, therea re 4 dehydrogenase enzymes that are producing reducing equivalents that will be shuttled to the electron transport chain to donate their electrons for the chemiosmotic gradient and ultimately ATP production through ATP synthase o A buildup of citrate is indicating that the electron transport chain has enough protons and therefore ATP in the cell (Citrate is the stopping point as a result) o Further, a buildup of citrate tells glycolysis in the cytoplasm that glucose and other monosaccharides do not need to be broken down at this point e) Insulin: o Up regulates 6PFK1 o Increases fructose-‐2,6-‐bisphosphate (Metabolite) and its enzyme = 6PF2K (This enzyme phosphorylates the second carbon of fructose-‐6-‐phosphate) à This is a shunt pathway in glycolysis o Fructose-‐2,6-‐bisphosphate is an allosteric regulator of 6PFK1 o Allosteric regulator definition: A metabolite that binds to a protein and modifies that protein to increase or decrease its activity o The cell sense the presence of insulin so that the enzyme for fructose-‐2,6-‐bisphosphate increases which tells the cell to produce more 6PF1K to allow more glucose to flow through the glycolytic pathway and have more of rapid conversion from fructose-‐6-‐phosphate à fructose-‐1,6-‐bisphosphate o Overall: Fructose-‐2,6-‐Bisphosphate acts upon 6PF1K as a result (An allosteric regulator of 6PF1K) so molecule will bind or interact with 6PF1K to increase its activity (NOT concentration) so allows for more rapid conversion from F6P to F-‐1,6-‐BisP • Third regulated step in glycolysis: -‐ PEP (Phosphoenolpyruvate) à Pyruvate via pyruvate kinase -‐ Points of regulation: a) ATP: o Down regulates pyruvate kinase activity o Sensing that the cell has enough energy at this point b) Alanine: o Down regulates pyruvate kinase o Pyruvate is the alpha keto acid of alanine (Alanine is deaminated or transaminated with the removal of NH 3 to produce pyruvate) o Therefore, a lot of glucose is not needed when there is a lot of alanine around o Alanine is abundant when eating protein sources o Glucose-‐Alanine Cycle: Occurs when there is an attempt to make glucose from peripheral tissues so that pyruvate à alanine à liver à gluconeogenesis, which slows down the glycolytic pathway (Alanine up regulates gluconeogenesis) c) Glucagon: o Down regulates pyruvate kinase o Signals for the release of glucose into the blood stream o Signals for the breakdown of glycogen and up regulates gluconeogenesis o Inhibits pyruvate kinase o Insulin levels are low when glucagon is present, therefore it is not necessary to have more products going through the glycolytic pathway when glucose is needed in the blood o When the liver senses glucagon, it will start breaking down glycogen (Muscle and liver) and initiating gluconeogenesis (Liver and little occurs in the kidneys) to breakdown to get free glucose d) Epinephrine: o Down regulates pyruvate kinase o Fight or flight hormone o Inhibits pyruvate kinase o Increases FA catabolism e) Fructose-‐1,6-‐bisphosphate: o Up regulates pyruvate kinase o Product of PFK1 so signals the up regulation of pyruvate kinase because if the cell is signaling for more PFK1 enzymes to be produced, it wouldn’t make sense to down regulate its follow up metabolism later in the glycolytic pathway o This is known as feed forward regulation—Here it’s necessary to up regulate pyruvate kinase to ensure that fructose-‐1,6-‐bisphosphate ends up at the end of the metabolic pathway o Feed forward regulation: When a compound regulates another reaction further down a pathway f) Insulin: o Up regulates pyruvate kinase o Facilitates post-‐translational modifications where enzymes will be phosphorylated or de phosphorylated to either increase or reduce the activity of that enzyme o With pyruvate kinase, insulin increases it via de-‐ phosphorylation • The prime difference between glycolysis and gluconeogenesis are the enzymes for the regulated steps à Even though most of gluconeogenesis is the reverse of glycolysis, it’s important for there to be different enzymes so that there won’t be a flow of molecules going through one of the pathways at the same time as the flow of molecules going through the other pathway (Inefficient) II. Gluconeogenesis • First regulated step in gluconeogenesis: -‐ Pyruvate à oxaloacetate via pyruvate carboxylase -‐ Points of Regulation: a) Acetyl CoA: o Up regulates pyruvate carboxylase o When one is consuming and using FA as an energy source, beta oxidation must occur which produces much acetyl CoA o In order to use acetyl CoA, oxaloacetate must be used to combine with acetyl CoA to form citrate in the TCA cycle o Running out of oxaloacetate is a concern since there is so much acetyl CoA production from beta oxidation because then the TCA cycle won’t continue to run o Ovearall: Pyruvate à oxaloacetate via pyruvate carboxylase partly for TCA cycle in the production of energy and in gluconeogenesis to make glucose since pyruvate is unable to go back to PEP (Oxaloacetate is able to be converted to PEP) • Second regulated step in gluconeogenesis: -‐ Oxaloacetate à PEP via PEP carboxykinase -‐ Points of Regulation: a) Insulin: o Down regulates PEP carboxykinase o When the liver or kidney senses insulin, there is a decrease in the concentration of PEP carboxykinase o The ubiquitin proteosomal pathway is used to decrease the number of PEP carboxykinases by degrading the enzymes and returning their AA parts to the AA pool • Third regulated step in gluconeogenesis: -‐ Fructose-‐1,6-‐bisphosphate à Fructose-‐6-‐Phosphate via fructose-‐1,6-‐bisphosphatase -‐ Points of Regulation: a) Fructose-‐2,6-‐bisphosphate: o Down regulates fructose-‐1,6-‐bisphosphatase because ample product is flowing through glycolysis b) AMP: o Down regulates fructose-‐1,6-‐bisphosphatase because it is signaling for an increase in PFK in glycolysis since the cell needs energy • Fourth regulated step in gluconeogenesis: -‐ Glucose-‐6-‐Phosphate à Glucose via glucose-‐6-‐ phosphatase -‐ Occurs in the liver and kidney only -‐ Points of Regulation: a) Insulin: o Down regulates glucose-‐6-‐phosphatase • Liver specifics: -‐ Glucose is taken up by the liver through GLUT 2 and uses purely facilitated diffusion à free glucose/fructose in the cell -‐ As free glucose comes into the cell, it’s important to phosphorylate glucose because a high concentration of free glucose will slow down the glucose uptake -‐ So phosphorylating glucose (or any other carbohydrate) will increase the amount of glucose taken up by the cell -‐ Fructose is able to enter as fructose-‐1-‐phosphate or predominantly as fructose-‐6-‐phosphate via glucokinase -‐ Liver wants to take up as much carbohydrate as possible because it’s going to break it down to pyruvate for ATP production (First) or it is going to store the glucose as glycogen or FA/triglyceride (Not all tissues are able to do this) à This all occurs (especially in the liver) to make the body as efficient as possible *Extra elaboration on the following slides in PPT 2-‐ 1/11/16 * Figure 12.9 • In the top left of the figure: Shows how glucose is entering the liver cell through GLUT 2 and how glucokinase is phosphorylating glucose à glucose-‐ 6-‐phosphate, which occurs primarily in the fed state • In the top right of the figure: Shows how in the endoplasmic reticulum (ER), there is an inorganic phosphate transporter, glucose-‐6-‐phosphatase, and a different glucose transporter for the ER facilitating the reverse process of reproducing glucose from glucose-‐6-‐phosphate -‐ The reverse process of producing glucose from glucose-‐6-‐phosphate in the cell occurs during times in the fasted state • Fasted State: -‐ Glycogen is broken down to glucose-‐6-‐phosphate à glucose o Glucose-‐6-‐phosphate that is produced in the cytoplasm from the breakdown of glycogen à ER where glucose phosphatase converts glucose-‐6-‐phosphate à glucose + inorganic phosphate -‐ Lactate à glucose-‐6-‐phosphate via gluconeogenesis process that must go through the ER as well o Other tissues and red blood cells generate lactate mainly because NAD+ must be regenerated as an electron acceptor in glycolysis involving the step from glyceraldehyde-‐3-‐phosphate à 1,3-‐ bisphosphoglycerate o Skeletal muscle generates lactate because of the lack of oxygen in high intensity movement; The lactate is transported back to the liver to go through gluconeogenesis • After glucose has been regenerated from glucose-‐6-‐phosphate in the ER, the glucose transporter T t3kes the free glucose to the membrane of the ER where GLUT 2 picks the glucose up and takes it to the cellular membrane to be released back into the blood stream to maintain blood glucose concentrations • Inorganic phosphate also has its own transporter in the ER so it can be reused for phosphorylation of other incoming glucose in fed state times Figure 12.10 (Slight review of previously discussed concepts) • Top portion of the figure (A): Insulin is present -‐ Fed state -‐ Insulin signals cell to take up glucose à glycolysis -‐ Specially showing the point where glucose àà fructose-‐6-‐phosphate à Fructose-‐1,6-‐bisphophate via 6PFK1 (Step 3) – Insulin up regulates this enzyme -‐ Serine residue of 6PF2K and insulin à Shunted Pathway: o Within 6PF2K, there is a specific serine residue that is de-‐ phosphorylated when insulin is secreted, which leads to the active form of 6PF2K that generates fructose-‐2,6-‐bisphophate from fructose-‐6-‐phosphate that up regulates 6PF1K so more glucose à pyruvate • Bottom portion of the figure (B): Glucagon and epinephrine are present -‐ Fasted state -‐ Pancreas has secreted glucagon to signal cells to break down glucose for energy -‐ Figure shows how pyruvate à oxaloacetate à PEP à fructose-‐1,6-‐ bisphosphate à fructose-‐6-‐phosphate via fructose-‐1,6-‐bisphosphatase (Part of the steps for gluconeogenesis discussed here) -‐ Serine residue of 6PF2K and glucagon: o Fructose-‐2,6-‐bisphophate is decreased in amount being produced because the serine residue of 6PF2K is phosphorylated à down regulation of 6PF1K and up regulation of fructose-‐2,6-‐phosphatase à fructose-‐6-‐phosphate -‐ Therefore, overall gluconeogenesis is up regulated + eventually get back to free glucose that can be used by tissues in the body (Especially red blood cells and the brain first) III. Glycogenesis • Glycogen synthase: Enzyme that creates glycogen from glucose à glucose-‐6-‐phoshpate (And other carbohydrate sources) • Glycogen synthase A: Activated version and is not phosphorylated • Glycogen synthase B: Less-‐active version and is phosphorylated • Points of Regulation: a) Insulin: -‐ Up regulates glycogen synthase A -‐ Insulin is secreted by the pancreas in the fed state after the consumption of a meal with carbohydrate, and insulin signals PIK3/Akt to down regulate glycogen synthase kinase 3 so that glycogen synthase A is not phosphorylated to produce glycogen synthase B -‐ Big picture: Insulin is an anabolic hormone that promotes glycogen synthesis so it is important for glycogen synthase A to be less active at this point b) Glucagon and epinephrine: -‐ Up regulates glycogen synthase B -‐ Secreted during the fasted state or due to a stress stimulus -‐ Requires the cAMP mechanism -‐ cAMP activates protein kinase A and phosphorylase kinase which causes the phosphorylation of glycogen synthase A à glycogen synthase B (Less-‐active version) -‐ Big picture: Glucose is needed in the blood and for energy when glucagon and epinephrine are present so glycogen stores are going to need to be broken down for the release of glucose c) Epinephrine: -‐ Up regulates glycogen synthase B -‐ Able to use PIP-‐Calcium mechanism as well -‐ Signals the phosphorylation of glycogen synthase à B version d) Other ways to inhibit the conversion of glycogen synthase B to glycogen synthase A when glucagon and epinephrine are present (Referring to bottom half of figure 12.15) -‐ Inhibitor 1A (Phosphorylated)—Less active version -‐ Inhibitor 1B (De-‐phosphorylated)—Active version -‐ Focus on top half of figure 12.15 though e) Depolarization of muscle cells: -‐ For muscle movement and contraction to occur energy in the form of ATP is needed -‐ ATP signals another kinase enzyme to phosphorylated glycogen synthase A à B -‐ Up regulation of glycogen synthase B is necessary so glycogen won’t be shuttled into storage but instead, the glucose can be used for ATP so the muscle can contract IV. Glycogenolysis • Glycogen phosphorylase: Enzyme that breaks down glycogen à glucose-‐6-‐phosphate à glucose • Glycogen phosphorylase B: Less active and de-‐phosphorylated • Glycogen phopshorylase A: Active and phosphorylated • Points of Regulation: a) Glucagon and Epinephrine: -‐ Up regulates glycogen phosphorylase A -‐ Use cAMP mechanism -‐ Glucagon presence in the blood activates protein kinase A, which phosphorylates phosphorylase kinase A that phosphorylates glycogen phosphorylase B (To give glycogen phosphorylase A = active) -‐ Review: Glucagon and epinephrine also signal for the phosphorylation of glycogen synthase A (Active) à B (Less active-‐ Makes glycogenesis less active and glycogenolysis more active) b) AMP: -‐ Up regulates glycogen phosphorylase B (Increases the activity of the enzyme) c) ATP: -‐ Down regulates glycogen phosphorylase B (Decreases the activity of the enzyme) d) Glucose: -‐ Down regulates glycogen phosphorylase A (Decreases the activity of the enzyme) -‐ Meaning that the breakdown of glycogen to glucose is not necessary since there is an influx of glucose V. PDH (Pyruvate Dehydrogenase) Complex • PDH: Enzyme used to convert pyruvate (product of glycolysis) à Acetyl CoA • General process: -‐ Pyruvate transporters transport pyruvate from the cytoplasm into the mitochondria where PDH is located -‐ Pyruvate à Acetyl CoA so acetyl CoA can be used in the TCA cycle to produce ATP from the reducing equivalents (3 NADH and 1 FADH ) 2 à electron transport chain for oxidative phosphorylation -‐ 1 NADH and 1 FADH 2are also produced with beta oxidation • Points of Regulation: a) NADH and Acetyl CoA (Allosteric regulators-‐ Metabolite that interacts with an enzyme by changing its confirmation but doesn’t create a bond) -‐ Ratio of NADH:NAD (Refer to top right of figure 12.18-‐ In terms of other processes such as beta oxidation producing NADH as well) -‐ Increased NADH (More than NAD ) down regulates PDH -‐ Decreased NADH (Less than NAD ) up regulates PDH -‐ Middle of figure 12.18: NAD acts as a substrate for pyruvate à acetyl CoA + NADH reaction -‐ NADH and acetyl CoA as ample products of the reaction down regulate PDH -‐ Example: Fasted state or ketogenic diet à -‐ Beta oxidation of FA is occurring at these points and are producing ample acetyl CoA as a result that is going through the TCA cycle and electron transport chain for energy production; Ample NADH is produced as a result of the TCA cycle -‐ Ample acetyl CoA and NADH from beta oxidation cause a buildup so these 2 products are not necessary to be produced by PDH through the conversion of pyruvate -‐ Concern about reduction in oxaloacetate that is necessary for the TCA cycle to keep working: § Because of the massive influx of acetyl CoA produced with beta oxidation, it is important for there to be enough oxaloacetate present § Carbohydrate Solution: Pyruvate is used instead to be converted à oxaloacetate via pyruvate carboxylase (Anaplerotic reaction-‐ A reaction that refills an intermediate of another pathway) § AA Solution: If no pyruvate is available, can deaminate AA and produce oxaloacetate directly (Acts as alpha-‐ketogenic acid) • Middle of figure 12.18: -‐ Active PDH is de-‐phosphorylated -‐ Less active form of PDH is phosphorylated • PDK (Pyruvate Dehydrogenase Kinase): -‐ Phosphorylates PDH to make it inactive (Indirectly regulates PDH) -‐ Different forms of PDK: 1, 2, 3, 4 (Be aware) -‐ Points of Regulation: a) Pyruvate: o Down regulates PDK o PDH will be up regulated and in the active state as a result b) Acetyl CoA:COA: o Up regulates PDK if there is an increased concenrration of acetyl CoA in the mitochodnria o PDH will be down regulated (via being phosphorylated by PDK) to less active version c) NADH:NAD : + o Up regulates PDK if there is an increased concentration of NADH in the mitochondria o PDH will be down regulated • PDP (Pyruvate Dehydrogenase Phosphate)-‐ PDP 1 and 2 -‐ Another enzyme used to indirectly regulate PDH -‐ Points of Regulation: a) Calcium: o Up regulates PDP to up regulate PDH o Secreted in muscle tissue during contraction which signals the cell that there is a demand of energy o Pyruvate à acetyl CoA reaction by PDH is up regulated as a result so acetyl CoA à TCA cycle b) Insulin: o Up regulates PDP to up regulate PDH o Although insulin is seen as an anabolic hormone, upon initial consumption of a meal, some ATP will be made for the immediate needs of that cell o Also, insulin promotes FAS with excess after the needs of the cell are met and acetyl CoA is necessary as a precursor for the creation of a FA VI. Lipid Metabolism (Review of general processes on the focus on TAG and FA) • Fed State: -‐ Consumption of mixed meal with lipid à digestion -‐ Lingual lipase: Digests TAG minimally in the mouth; st rd Hydrolyze FA at the 1 and 3 carbon -‐ Gastric lipase: Digests TAG minimally in the stomach à TAG, DAG, and MAG; Hydrolyze FA at the 1 and 3 carbon -‐ Pancreatic lipase and colipase: Secreted by the pancreas -‐ For pancreatic lipase and colipase to function, it is necessary for bile to be released from the gallbladder into the proximal portion of the small intestine to help emulsify lipids -‐ Bile: Composed of emulsifiers = Cholesterol, phospholipids, and bile acids -‐ With mostly TAG + also some DAG and MAG coming from the stomach + bile à Micelle production where the outer surface is composed of phospholipids, bile acids, some cholesterol and the core = DAG, MAG, TAG -‐ Effectively malese lipids soluble in water as a result by bile -‐ Process: Colipase: Binds to the surface of micelle onto the bile acids, which allows for the binding of pancreatic lipase-‐ Functions to hydrolyze FA from DAG and TAG that are attached to micelle -‐ The products of pancreatic lipase (Which are then officially put into the micelle) = 2 Free FA + MAG à The micelle is then able to be taken up by the enterocyte -‐ So the enterocyte has taken up 2 MAG and 2 free FA where the next step is to re-‐esterify the 2 FA on MAG to TAG again à Formation of chylomicron -‐ Chylomicron: A lipoprotein (Used for the transport of lipids in the blood—because it’s in a water/aqueous environment); Formed in the small intestine and their specific function is to transport TAG from the diet (Exogenous) to tissues first via the lympathic system—by passes the liver -‐ After the chylomicron delivers the TAG to the necessary tissues, the chylomicron remnant then goes back to the liver to be broken down in order to use its components for VLDL synthesis or energy metabolism -‐ Liver: Makes FA and TAG à VLDL formed for the transport of endogenous TAG (TAG that is contained in body) -‐ As mentioned before, esterification of FA onto glycerol produces TAG -‐ VLDL synthesis of TAG and secretion in the blood -‐ In the blood, have lipoproteins that are carrying TAG to be deposited in skeletal muscle, adipose tissue à In times of energy need, can take to muscles or other tissues that need ATP and if fulfill need, can take to adipose tissue to be stored for a later time -‐ Enzyme responsible for breakdown of TAG (Endogenous) contained within lipoproteins = Lipoprotein lipase (LPL)— Hydrolyzes FA from TAG so the FA are transported across membrane into the cell where they can be used for ATP or storage (Depends on state of cell—but for the fed state, they will be stored) • Fasted State: -‐ No digestion occurs because not consuming a meal here -‐ Right side of figure 16.1 in adipose tissue: o Store lipids as TAG o Need to break down TAG into FA and glycerol so it can be transported across the plasma membrane and be carried into the blood to be carried to tissues to be used for energy production -‐ Enzyme to breakdown TAG in adipose tissue: Hormone Sensitive Lipase à AKA: Adipose Tissue TAG Lipase; Essentially know that there is a lipase in adipose tissue that is responsible for breaking down TAG into free FA and glycerol so these can be transported across membrane -‐ Glycerol is freely soluble and be carried in the blood as is -‐ FA must be carried in the blood by albumin to whatever tissue needs the FA -‐ Skeletal muscle: o Will be using lipids in two different manners o There is some storage of TAG in some muscle (Intramuscular TAG) à Can be used for ATP o Can take up FA from the blood and use for ATP production as well (Ketone bodies apply here too) o Largely going to be a user of FA -‐ Liver: o Central processing organ that will sense how much energy is in the body and what we need to do to survive o Fasted State means that the body as a whole needs energy o Liver will secrete glucose from glycogenolysis first to fulfill energy needs and maintain blood glucose concentrations o Continue in progression: HSL of adipose tissue breaks down TAG and secretes 3 free FA and glycerol into the blood, it will take a while for these products to get back to the liver o Glycerol goes back to the liver where it will be used in gluconeogenesis to secrete glucose into the blood to maintain blood glucose concentrations o IDL and LDL come back to liver with other types of lipids (Not focusing on these though) o 3 free FA (Focus) coming back to liver through albumin: Depending on the state and how long have been fasting, FA will go back into VLDL synthesis (Re-‐esterified onto glycerol à make VLDL) to be secreted back into the blood o Any tissues with mitochondria can use FA o Depending on how long been fasting, get into ketone synthesis à When carbohydrate supply is low o The brain is a primary user of ketones o Glucose starts running low, the liver is signaled by the body that it still need energy so the cells that can’t use FA as an energy source, ketone bodies are produced in the liver that are secreted into the blood to tissues with mitochondria o Ketone Bodies: Acetone, Beta hydroxybutyrate, Acetoacetate o Beta hydroxybutyrate and acetoacetate are used for energy production; Used interchangeably as ketone bodies (Interconverted) à The concentration of either is dependent on the NADH concentration in the mitochondria o Acetone is aspired off in the lungs (Not used for energy production) o Ketone bodies: Think acetoacetate and beta hydroxybutyrate (Don’t think it’s one or the other because it depends on the mitochondria state) o FA à Ketone Body via beta oxidation (Acetyl CoA is produced as the precursor for FAS) o FA that come into the liver in fasted state, will go through beta oxidation for energy production and if the liver has met its energy demands, there is a build up of acetyl CoA o Acetyl CoA will be used to make acetoacetate and beta hydroxybutyrate to be secreted in the blood to the appropriate tissues that will convert the ketone bodies back to acetyl CoA to be used in the TCA cycle -‐ Heart: o Excellent oxidizer of lipids o Uses lipids as a primary energy source (Whether it’s FA or ketone bodies) because it’s a highly aerobic tissue VII. Lipid Regulation (Factors into carbohydrate regulation) • Fed State: Insulin regulation -‐ Points of Regulation: a) Lipoprotein lipase (LPL)-‐ Used to hydrolyze FA from TAG to be taken into the corresponding cell: o Insulin up regulates LPL o LPL breaks down TAG in both chylomicrons and VLDL (Clears lipid from the blood so it can be stored or used) o Enzyme relates to fed state b) Pyruvate (FAS relation): o Insulin increases glucokinase/hexokinase, PFK, and pyruvate kinase in glycolysis that all contribute to producing pyruvate o Insulin signals glycogenesis o Pyruvate à acetyl CoA via PDH, which is used in FAS o Insulin therefore up regulates FAS à palmitic acid o Key because a build up of FA in the liver is toxic so progressive storage of FA is necessary c) Making TAG and secreting VLDL: Once again, related to LPL • Fasted State: Glucagon and Epinephrine regulation -‐ Points of Regulation: a) HSL (Hormone Sensitive Lipase) o Glucagon and epinephrine up regulate HSL o Occurs in a time of energy need (Fasted state) • Regulation of FAS: -‐ Basics of FAS: o Pyruvate à Acetyl CoA à Citrate (In mitochondria) à Back to cytoplasm à Re-‐converted to acetyl CoA à Malonyl CoA à FA (2 Carbons are added on at a time to initially produce palmitic acid 16:0) o Acetyl CoA Carboxylase: One of the enzymes contained within the FA synthase enzyme complex that is important for the initiation of FAS o Phosphorylated Acetyl CoA Carboxylase: Less active version—Occurs because of AMP-‐activated protein kinase o De-‐Phosphorylated Acetyl CoA Carboxylase: Active version – Occurs because of protein phosphatase 2A -‐ Points of Regulation: Acetyl CoA Carboxylase a) Insulin: o Up regulates protein phosphatase 2A that up regulates acetyl CoA carboxylase o Up regulates protein phosphatase 2C that prompts the conversion of AMP-‐activated protein kinase (high activity) to the low activity version so that acetyl CoA carboxylase is able to be more active in initiating FA synthesis b) Citrate: Allosteric regulator o Up regulates de-‐phosphorylated active acetyl CoA carboxylase o TCA cycle intermediate that also is a precursor for FAS (When citrate is converted back to acetyl CoA à cytoplasm) o Occurs because citrate favors à FA when there is a buildup of citrate and reducing equivalents in the TCA cycle o Review: Citrate buildup also indicates signaling in slowing down glycolysis c) Fatty Acyl-‐CoA: Allosteric regulator o Down regulates acetyl CoA carboxylase à phosphorylated less active version o The bond between fatty acyl and CoA is a high energy bond (An activated FA—energy was required to activate it) o Fatty acyl-‐CoA is also a precursor for other lipid classes o Focus on fatty acyl-‐CoA à TAG in this case o A buildup of FA-‐CoA down regulates acetyl CoA carboxylase ?
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