Class Note for BIOC 460 at UA 2
Class Note for BIOC 460 at UA 2
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Metabolic Integration 1 Key Concepts Metabolic pro les of major organs Metabolic homeostasis and signaling Metabolic adaptations to starvation KEY QUESTION IN METABOLIC INTEGRATION How do the pancreas liver skeletal muscle and adipose tissues control serum glucose levels Metabolic profiles of major organs Bioc 460 Dr Miesfeld Spring 2008 Bod sha e isim ortant We have focused primarily on cellular biochemistry up to this point now we turn our attention to physiological biochemistry which involves metabolic integration throughout the organism We will use humans as our organism of choice for this discussion but of course metabolic integration is critical for all multicellular organisms and even for single cell organisms such as yeast and bacteria which colonize environmental niches and depend on cellcell communication The metabolic map in gure 1 has been streamlined to better illustrate how the three major sources of metabolic fuel in our diets carbohydrates lipids fats and protein contribute directly to ATP production This version of the metabolic map emphasizes five energy conversion processes that we have discussed in some detail 1 carbohydrate metabolism glycolysis and gluconeogenesis 2 lipid metabolism fatty acid oxidation and synthesis 3 amino acid metabolism oxidation and synthesis 4 the citrate cycle and 5 oxidative phosphorylation Note that liver cells can perform all of the synthesis and degradation reactions shown in gure 1 however most other cell types are primarily limited to catabolizing glucose and fatty acids to igure 1 F J Carbohydrate l T Metabolism triglycerides T Lipid Amino Metabolism Acids Glucose glycerol Ammo Actd i T Metabolism glyceraldehyde 339P l Fatty 4 T Acids Pyruvate b co2 AcetylCoA gt ketone bodies A oxa loa cetate Citrate Cycle NH4 C02 NADH FADHZ ADP Pi 02 gZLZZZZyIation H20 generate ATP through mitochondrial oxidative phosphorylation reactions The term energy balance relates energy input in the whole organism to energy expenditure Positive and negative energy balance is determined by the energy content of the metabolic fuels ingested compared to the amount of energy expended through endergonic chemical reactions physical exertion and thermogenic processes In the simplest case energy balance is achieved when energy input measured in kilocalories also referred to as quotfoodquot Calories 1 of 14 pages Bioc 460 Dr Miesfeld Spring 2008 1 Calorie 1 kilocalorie 4184 kilojoules equals energy expenditure on a daily basis Note that the relative proportions of carbohydrate fat and protein in our diets needs to be optimized to prevent metabolic disorders that can occur even under conditions of Caloric energy balance For example obtaining too many daily Calories from saturated fats can lead to cardiovascular disease whereas excessive amounts of protein can cause nitrogen toxicity due to NH overload The utilization of various metabolic fuels by different organs in the human body is controlled at the cellular level as a function of nutrient availability Some of these biochemical processes are developmentally determined cellspecific expression of required enzymes while others are controlled more acutely by hormonal signaling through receptor proteins Two of these hormones are insulin and glucagon which we have discussed numerous times throughout the course Another important signaling pathway we introduce here is one that controls interorgan metabolic flux through a subfamily of nuclear receptors known as the peroxisome proliferatoractivated receptors PPARs The PPARs are a family of transcription factors PPARy PPARa PPARB that regulate gene expression in response to activation by fatty acidderived ligands PPARs are targets for a new class of pharmaceutical drugs used to treat metabolic disorders including type 2 diabetes Figure 2 shows the location and function ofthe primary tissues and organs in the human body that play a direct role in metabolic flux In addition to the liver muscle skeletal and heart Figure 2 Brain nonspmts ions to Pancreas maintain membrane potential integrates inputs from body and surroundings sendssignals to Lymphoiic other organs system Seuetes insulin and glucagon in response to changes in blood glucose concentration Processes rats taioohydistes proteinslrom diet synthesizes and distributes lipids ketone bodiesand glucose for other tissues converts excess nitrogen to urea Carrieslipids irorn intestine to liver Adipose quot55 synthesizes storesiand mobilizes Poriai vein l f quotanyl quot wt 39 R V l cerols Carriesnutriems Q f i y from intestineto liver K Small intestine Uses ATP 0 do mechankal work 1 adipose brain and kidney which are described below several other organs play an important supporting role in metabolic integration One of these is the pancreas which secretes insulin and glucagon in response to changes in serum glucose levels and also produces a variety of proteases Absnrbs nutrients from the die moves them into blood or lymphatic system 2 of 14 pages Bioc 460 Dr Miesfeld Spring 2008 that degrade dietary proteins in the small intestine trypsin chymotrypsin elastase Also shown in figure 2 is the small intestine which is an critical component of the gastrointestinal tract because it serves as the major site of dietary nutrient absorption The large intestine or colon absorbs water and electrolytes and also secretes a neuropeptide called PYY33936 that controls eating behavior The stomach prepares food for the small intestine by initiating the digestive process through protein hydrolysis at a low pH in the presence of the protease pepsin Moreover the stomach secretes a neuropeptide called ghrelin that sends hunger signals to the brain Let39s look a little more closely at the key metabolic organs in humans LIVER The liver serves as the central processing facility and metabolic hub of the body by determining what dietary nutrients and metabolic fuels are distributed to the peripheral nonliver tissues The liver also functions as a physiological glucose regulator that helps remove excess glucose from blood when carbohydrate levels are high and releases glucose from stored glycogen or as a product of gluconeogenesis when serum glucose levels are low Serum glucose regulation by the liver is controlled primarily through the insulin and glucagon signaling pathways which modulate metabolic flux through glycolysis gluconeogenesis and glycogen metabolism With the exception of dietary triacylglycerols that are transported from the small intestine to peripheral tissues by chylomicrons that enter the lymphatic system most nutrients absorbed in the small intestine are delivered directly to the liver via the portal vein This anatomy explains why the liver plays such a key role in coordinating the distribution of dietary nutrients as it is the first organ to inventory the contents of your last meal A large proportion of the dietary monosaccharides delivered by the portal vein are retained by the liver in the form of glucose6phosphate following phosphorylation of glucose by the enzymes hexokinase or glucokinase As shown in figure 3 glucose6phosphate has several Figure 3 Released into the blood Glucose6 phosphatase Glucose6P dehydrogenase Phosphogluco PhOS ho mutase gt E ltEfr Glucose 396P Glucose1P NADF39 J l 1 ll Phosphoglucose NADPH H J co en PentoseP M isomerase y g synthesrs pathway i Fructose 1P i Glycolysis Pyruvate Pyruvate dehydrogenase Ketogenesis AcetyI CoA Lipid it b 39 th 39 my es Oxidative phosphorylation fates depending on the metabolic needs of the liver and the peripheral tissues Most of the glucose6phosphate is used to synthesize liver glycogen following its isomerization to glucose1 phosphate by the enzyme phosphoglucomutase Glucose6phospate can also be dephosphorylated in the liver by glucose6phosphatase and released into the blood to be used by other tissues in particular the brain lf liver cells are in need of NADPH for biosynthetic reactions then glucose6phosphate is converted to 6phosphoglucolactone by glucose6P dehydrogenase in the first reaction of the pentose phosphate pathway Lastly glucose6phosphate can be converted to fructose6 phosphate by phosphoglucose isomerase and then metabolized by the 3 of 14 pages Bioc 460 Dr Miesfeld Spring 2008 glycolytic pathway and the pyruvate dehydrogenase reaction to yield acetylCoA for use in lipid biosynthesis oxidative phosphorylation or ketogenesis MUSCLE The human body contains two types of muscle tissue that play a major role in metabolic integration 1 skeletal muscle which utilizes different amounts of free fatty acids glucose or ketone bodies for metabolic fuel depending on the physical movements required rapid burst of activity or endurance activity and 2 cardiac muscle which uses mostly fatty acids and ketone bodies as metabolic fuel to sustain a steady heart beat which averages over 100000 beats per day During the resting state skeletal muscle primarily uses fatty acids released from adipose tissue as a source of energy The fatty acids are oxidized to generate acetylCoA which is then used by the citrate cycle to produce reducing power NADH and FADH2 for oxidative phosphorylation However when muscle contraction is required for a very short burst of activity for example serving a tennis ball to your opponent 23 seconds the exercising muscles make use Figure 4 of the intracellular ATP pool If a more sustained 39339 level of muscle activity is needed such as a short o io sprint across the tennis court to return a serve NH during NH2 8 seconds then the ATP pool is replenished With l activity ATP made by a phosphoryl transfer reaction using CINH2 ADP during ATP cl NHZ phosphocreatine figure 4 The creatine CHs I39 recovery CHs lil kinase reaction is readily reversible and catalyzes CH2 CH2 the resynthesis of phosphocreatine when cellular coo Cloc ATP levels return to normal during muscle phosphocreatine Creatine recovery Most of the stored glycogen in humans exists in muscle tissue that is spread throughout the body However unlike the liver that contains 10 glycogen by weight individual muscle groups contain only 1 glycogen by weight Therefore glycogen stores in any one muscle group become depleted when muscle contraction continues beyond about an hour As glucose levels decline the muscle tissue becomes more dependent on fatty acids released from adipose tissue and on ketone bodies produced in the liver to maintain the high rates of ATP synthesis needed for contraction Muscle cells lack fatty acid synthase and glucose6phosphatase which means that they can neither synthesize fatty acids for export to other tissues nor release glucose from glycogen degradation In this regard muscle is truly a selfish tissue using energy made available from other parts of the body for its own purpose of mechanical movement Note however that during long term starvation skeletal muscle can be used as an energy source for the body by providing amino acid substrates for liver and kidney gluconeogenesis as described later ADIPOSE TISSUE Adipose tissue was once thought of as a simple fat depot in the body that stores and releases fatty acids from adipocytes fat cells in response to metabolic needs However it is now known to be an active player in metabolic integration serving as an endocrine organ that secretes peptide hormones called adipokines adipocyte hormones As described later adipokines are key regulators of metabolism and control important immunological neurological and developmental functions in the body Adipose tissue is widely distributed throughout the body making up 15 25 of the mass of an individual and accounts for over 500000 kJ of stored energy Although adipocytes are present in many parts of the body for example near skeletal muscle surrounding blood vessels and in the mammary gland there are two locations in the body where the majority of adipose tissue can be found One is subcutaneous fat that is located just below the skin 4 of 14 pages Bioc 460 Dr Miesfeld Spring 2008 surface most noticeable in the thighs buttocks arms and face The other is visceral fat which lies deep within the abdominal cavity and is responsible for the size of your waistline The biochemical and endocrine functions of visceral fat and subcutaneous fat are distinct which explains why the physiological consequences of extra body fat is not the same for everyone One way to predict if someone has too much body fat is to determine their body mass index BMI using a ratio oftheir weight and height BMI values are derived by dividing the weight in kilograms ofa person by the square oftheir height in meters Body Mass Index BMI weight kgheight m2 It is generally accepted that a BMI value of less than 185 is considered undenveight 185 25 is within the normal weight range 2530 is ovenNeight and greaterthan 30 is obese lmportantly a BMI value is only an approximation of stored fat since it cannot distinguish between body weight due to excess fat stores or a large muscle mass gure 5 Moreover BMI values do not provide information about the relative amounts of visceral fat and subcutaneous fat stores Despite these shortcomings epidemiological studies have shown that on average people with a BMI value of gt30 have a higher risk ofdeveloping type 2 diabetes heart disease and cancer as a result of metabolic conditions associated with obesity Because Fiqure 5 adipokines produced in visceral fat Height 60 60 60 contribute to the development of Weight 240 lbs 240 lbs 240 lbs obesityrelated diseases one of the Waist 32 in 44in 38in best ways to predict an individual39s quotquotPS 30 in 38 in 44 in disease risk is to use both their BMI value and a quantitative measurement of body fat distribution as determined Sf ml by the circumference of a their waist i in relationship to the size oftheir hips K at it By determining a person39s waist to hip g f i ratio WHR it is possible to obtain an H a roximate measurement ofthe pp Muscular shape Apple shape Pearshape relative amounts of Visceral and F at stores Very little Visceral Subcutaneous subcutaneous fat stored on their BM 325 325 325 body A high WHR value corresponds WHR 106 115 085 to an quotappleshapedquot body more CVD risk Low VeryHigh High visceral fat in the waist than subcutaneous fat on the hips whereas a low WHR value leads to a quotpearshapedquot body An explanation for why disease risks are elevated in ovenveight people with a high WHR is that increased amounts of visceral fat alters the expression of certain adipocyte hormones such as leptin tumor necrosis factor a TNFot and adiponectin High levels of visceral fat lead to increased expression ofthe leptin and TNFx genes with reduced expression of adiponectin We will look more closely at the biochemical processes underlying the connection between adipose metabolism adipokines and human metabolic disease later in the chapter Adipose tissue is responsible for regulating the triacylglycerol cycle which is an inter organ process that continuously circulates fatty acids and triacylglycerols between adipose tissue and liver As illustrated in figure 6 there are two parts to the triacylglycerol cycle 1 the systemic component that recycles fatty acids released from adipose tissue by hormonesensitive lipase and 5 of 14 pages Bioc 460 Dr Miesfeld Spring 2008 triacylglycerols synthesized in liver cells and 2 the intracellular component that recycles fatty acids that enter adipocytes following triacylglycerol hydrolysis by lipoprotein lipase and triacylglycerols synthesized inside adipocytes Under normal conditions 75 the free fatty acids released by hormonesensitive lipase in adipocytes is returned to lipid droplets as triacylglycerols through either the systemic or Triacylglycerol intracellular routes The metabolic relevance of the triacylglycerol cycle is not completely understood but it may provide a mechanism to Glycerol l Fu lfor maintain a pool of free fatty acids that can be 3phosphate tissues readily used for metabolic fuel in peripheral tissues such as skeletal muscle Figure 6 Adipose tissue Blood Liver Lipoprotein lipase Glycerol Triacylglycerol Fatty acid Glycerol 3phosphate BRAIN The brain is the control center of our bodies consisting of 100 billion nerve cells neurons that transmit electrical information along the neuronal axon using action potentials that are driven by changes in charge distribution across the plasma membrane The key to these electrical impulses are ions that cross the membrane through channels that are controlled by neurotransmitter substances such as acetylcholine that function as signaling molecules between adjacent neurons The steadystate electrical charge across the membrane is maintained by ATPdependent ion pumps most importantly the NaquotK ATPase ion transport protein Based on studies using oaubain to inhibit the NaJ39K ATPase transporter up to half of all the ATP generated in the brain goes toward keeping this critical ion pump fully active Studies have shown that about 20 of the oxygen consumed by the body is used for oxidative phosphorylation in the brain Moreover the brain requires as much as 120 grams of glucose each day which accounts for 60 of the glucose used by our bodies under normal conditions The brain39s dependence on glucose is illustrated by the dizzy feeling you experience when your serum glucose levels fall from normal levels of 45mM 80 mgdl to 35mM 60 mgdl as a result of glycogen depletion brought on by prolonged intense exercise The brain unlike most other organs is exclusively dependent on glucose under normal conditions to provide the necessary chemical energy for ATP production Fatty acids cannot cross the bloodbrain barrier because they are bound to carrier proteins however the energyrich ketone bodies acetoacetate and DShydroxybutyrate are able to enter the brain Since the brain has no energy stores of its own the demand for glucose to maintain brain function must be met by the liver which devotes much of its ATP to generating glucose for the brain via the gluconeogenic pathway During prolonged starvation when glucose levels are abnormally low the brain adapts to using ketone bodies to supply the acetylCoA needed for ATP synthesis by oxidative phosphorylation CIRCULATORY SYSTEM Metabolic integration within the human body depends on the redistribution of metabolites ions and hormones between the various tissues This is the job of the circulatory system which consists of 150000 kilometers of blood vessels that deliver six liters of blood to cells through a complex network of microcapillaries The circulatory system links together the major tissues and organs of the body in such a way that biochemical pathways in different cells share metabolites to ensure that the metabolic efficiency of the whole organism is greater than the sum of the parts Figure 7 6 of 14 pages Bioc 460 Dr Miesfeld Spring 2008 summarizes the primary metabolic pathways in six major tissues and organs of the human body under normal homeostatic conditions It can be seen that the liver is the control center of this metabolic network and plays a crucial role in regulating metabolite flugtlt between tissues and organs One of the primary roles of the liver is to export glucose and triacylglycerols to the peripheral tissues for use as metabolic fuel The brain has arguably the most importantjob of all in Figure 7 HEART BRAIN A Glucose KIDNEY C0 H20 AcetyeroA p rtvm f y ATP Oxaloacetatea lucose Pymtvate Mimic 4 CO2 H20 arketoglutarate Glucose Fatty acld NHf gt v ExcrefEd G y em Urea Amino acids LIVER ADIPOSE Glngen lt Glucose E3312 Glucfse 7 l T 1 DHAP ISM PYWVGIE gtAcetyeroA a 5 7 Glycerolr3P 1 L Lactate DHAP r protein Fatty acid G39YCEFOHP Fatty acid Trlacyglycerol Glycerol TriuKyglyrerol Glycerol Glycerol SKELETAL MUSCLE Lacme Fattyacid Amino 1 l t i Pyruvate gt AcetyICoA AT 02 Hzo Protein T ATP Glucose Z Glycogen terms of defining life but metabolically speaking it is an energy drain on the system that requires a constant input of glucose one of the body39s most precious metabolites Cardiac muscle makes use of fatty acids and ketone bodies for most of its energy needs but also uses glucose at a low level The exchange of fatty acids and triacylglycerols between the liver and adipocyte tissue constitutes the triacylglycerol cycle Skeletal muscle uses glucose and fatty acids derived from the 7 of 14 pages Bioc 460 Dr Miesfeld Spring 2008 liver and dietary sources for ATP synthesis whereas it exports lactate back to the liver to complete the Cori Cycle during times of prolonged physical exertion lmportantly the amino acids glutamine and alanine transport excess nitrogen obtained from protein degradation in the muscle to the liver and kidney for excretion as nitrogen waste in the form of urea It is easy to see that abnormal function in one tissue or organ will have metabolic consequences in other parts of the body Indeed it is the primary task of physicians with training in internal medicine to unravel the biochemical and physiological bases for altered metabolic interactions in their patients Metabolic homeostasis and signaling In order to cope with constant changes in the environment our bodies must be able to maintain a metabolic state that optimizes available energy stores For example the brain requires a constant supply ofglucose to ensure high fidelity neuronal transmissions and skeletal muscle must have enough glycogen on hand to permit rapid muscle contraction in response to imminent danger or a chance to obtain food Similarly adipose tissue must be able to control the release and storage of triacylglycerols obtained from the diet or generated from carbohydrates in the liver to effectively manage this high energy metabolic fuel Metabolic homeostasis describes steadystate conditions in the body and can apply to a wide variety of physiological parameters These include glucose lipid and amino acid levels in the blood electrolyte concentrations blood pressure and pulse rate During times of physical activity psychological stress orfeeding biochemical processes are altered to counteract the effects ofthese environmental stimuli in an attempt to return the body to metabolic homeostasis Regulation of metabolic homeostasis requires both neuronal signaling from the brain and the release of small molecules into the blood that function as ligands for receptormediated cell signaling pathways Two of the most important global metabolic regulators in humans are the peptide hormones insulin and glucagon both of which are secreted by the pancreas Insulin and glucagon are the quotyin and yangquot ofglucose homeostasis in that they have complementary but opposing functions in controlling serum glucose levels Insulin and glucagon are synthesized as prohormones in a region of the pancreas called the islets of Langerhans which was named after the German medical student Paul Langerhans 59M who first described these hormonesecreting cells in 1869 7 375 There are three cell types in the islets of Langerhans that Pancreas 1quot quot739 an produce peptide hormones figure 8 The 3 cells which 5 ex make up the majority of cells in this region of the pancreas I 7x 739 are responsible for insulin secretion whereas the a cells yquot secrete glucagon Athird cell type the 3 cells produce 397 ycegucagon somatostatin which is paracrine hormone that functions n l 5 9quot locally to control the secretion of insulin glucagon and h 1135 7 V I nsu39m digestive proteases In addition to hormone secretion by Blood 39 39 39 39 cells in the islet of Langerhans the pancreatic acinar cells Vesse39s in the pancreas secrete digestive proteases into the pancreatic duct which connects to gastrointestinal track I w I As shown in figure 9 insulin signaling stimulates quot quot 6 cell glucose uptake in liver skeletal muscle and adipose tissue mamstati as well as activating fatty acid uptake and triacylglycerol storage in adipose tissue Glucose uptake in liver cells is primarily due to increased metabolic flux through glycolytic glycogen synthesis and triacylglycerol synthesis pathways Besides activating glycolysis and glycogen synthesis in skeletal muscle cells insulin also stimulates translocation of the GLUT4 glucose transporter protein to the plasma membrane In adipose tissue insulin 8 of 14 pages Bioc 460 Dr Miesfeld Spring 2008 signaling leads to GLUT4 translocation and increase rates of fatty acid uptake and triacylglycerol storage As described later in the chapter insulin stimulates neuronal signaling in the hypothalamus region of the brain that controls eating behavior and energy expenditure Glucagon signaling in livertissue stimulates glucose export as a result of increased rates of gluconeogenesis and glycogen degradation whereas in adipose tissue glucagon activates triacylglycerol hydrolysis and fatty acid export Note that skeletal muscle and brain cells lack appreciable levels of glucagon receptors and are considered to be glucagon insensitive First discovered in the early 1990s the PPAch PPARy and PPARo nuclear receptor Figure 9 Tissue Insulin Signaling Glucagon Signaling Liver Stimulates glucose uptake by Stimulates glucose export by Skeletal muscle Adipose Brain increasing metabolic llux through glycolysis glycogen synthesis and triacylglycerol synthesis pathways Stimulates glucose tiplake by increasing the level ol GLUT l transporter protein on the cell surface and also by increasing ux through glycolysis and glycogen synthesis pathways Stimulates glucose uptake by increasing the level ol GLUT4 leading to increased rates or fatty acid and glycerol synthesis activates fatty acid uptake from VLDL particles and promotes triacylglycerolstorage Stimulates neuronal signaling in the hypothalamus that leads to decreased eating and increased energv expenditure increasing metabolic ux through gluconeogenesis and glyeogen degradation pathways No effect Stimulates fatty acid export by activating triacylglycerol hydrolysis at the surface of lipid droplets No effect proteins are now known to be key players in controlling metabolic homeostasis in humans However unlike the insulin and glucagon receptors that rapidly activate intracellular phosphorylation signaling cascades in response to high affinity endocrine hormones the PPARs function as transcription factors that regulate gene expression in response to the binding of low affinity fattyacid derived nutrients such as polyunsaturated fatty acids and eicosanoids gfigure 10 This property of PPARs makes them ideal metabolic sensors of lipid homeostasis and results in long term control of pathway flux by directly altering the steadystate levels of key proteins The name quotperoxisome proliferatoractivated receptor was originally Plasma 39 membrane Nuclear membrane Figure 10 Fatty acid derived molecule 3 Fatty acid binding protein Ligandactivatio of PPAR RXR expression am Lipid metabolizing gene Lipid transport FA oxidation 1 FA synthesis Thermogenesis I Insulin sensitivity 3 Egg Lipid metabolizing enzyme f Protein synthesis 9 of 14 pages Bioc 460 Dr Miesfeld Spring 2008 coined to describe PPAROi which was discovered in Figure 11 rat hepatocytes as the mediator of peroxisome CH3 CH3 biogenesis in response to the drug clofibrate o l Clofibraterelated drugs fibrates have been used all V V y to treat high serum cholesterol in humans and 0 CH3 31 even though they do not cause peroxisome GemfibrozilPPARaseIeciivei proliferation in human hepatocytes the name has CH3 0 stuck and been applied to the other two members m 39c K of this family PPARy and PPARE Hac jg A JR j isx NH PPARs have a variety of functions in lipid N 0 5 metabolism ranging from regulation of lipid Rm39gmmPPARyse39eCt39VE transport and mobilization to fatty acid oxidation CH3 and lipid synthesis They also play an important 402ch f role in energy metabolism and insulinsensitivity One of the most important functions of PPARy is to s 3Q CF3 control adipocyte differentiation and lipid synthesis GW501516PPAR55elective N in adipose tissue but it also regulates insulin ch sensitivity in all three tissues as well as lipid Figure 12 synthesis in liver cells PPARy is the therapeutic target of thiazolidinediones TZDs which improve p i n insulinsensitivity in type 2 diabetics by activating PPARy target genes involved in lipid synthesis The PPARs represent an attractive class of protein targets for the development of pharmaceutical drugs for treating human metabolic disease Not only are they responsible for controlling lipid homeostasis in liver and adipose tissue but they also regulate glucose metabolism and thermogenesis in skeletal 0 muscle lndeed both fibrates and TZDs were used to treat cardiovascular disease and diabetes 3 respectively well before they were known to be PPAR ligands However a problem with some of the PPAR agonists is that they can bind to more than one ngl fltjdg g ign taEill Otivrjingsligon PPAR family member which can lead to undesirable p p p Side effects Figure 11 shows the chemical Fi we 1339 structure of three PPARselective agonists that have been developed to address this problem Gemfibrozil is a PPARocselective fibrate currently in use to treat high cholesterol in patients and rosiglitazone is a TZD compound that binds with high affinity to PPARy and is used to treat type 2 GW2433 diabetes The PPARoselective agonist GW501516 V V has been evaluated in human clinical trials for the treatment of atherosclerosis and obesity by altering Q flux through lipid metabolic pathways One of the biggest challenges in developing selective PPAR ligands is that the hydrophobic pocket in the C terminal ligand binding domain is unusually large 10 of 14 pages Bioc 460 Dr Miesfeld Spring 2008 for a nuclear receptor For example as shown in figure 12 the ligand binding domain of human PPARo can accommodate the 033 polyunsaturated fatty acid eicosapentaenoate all cis 205 A5 8 11 14 17 in eitherthe tailup or taildown orientation indicating that the hydrophobic pocket is shaped like the letter quotYquot This prediction was confirmed by the PPARo protein structure shown in figure 13 where it can be seen that the synthetic PPARdPPARa agonist GW2433 is able to completely fill the binding ligandbinding pocket Metabolic adaptations to starvation Figure 14 Metabolic adaptation to food shortages has been 24 hour fast presened over evolutionary time to ensure sunival during famine The human body adapts to these g T Kemnebodm near stanation conditions by altering the flux of 39 metabolites between various tissues in order to extend life as long as possible The primary metabolic challenge is to provide enough glucose forthe brain to maintain normal neuronal cell functions Although fatty acids released from 39 quot adipose tissue are plentiful in the blood the brain 0 Hoursgfzfas ng 24 cannot use fatty acids for metabolic fuel because they cannot cross the bloodbrain barrier Red blood cells erythrocytes are also dependent on serum glucose as a sole source of energy to generate ATP Mature erythrocytes lack mitochondria and therefore are not able to utilize fatty acids for energy because fatty acid oxidation takes place in the mitochondrial matrix The glucose required at the onset of stanation 24 hour fast is initially supplied by the degradation of liver glycogen in response to Fattyadds glucagon signaling however this form of metabolic 0 1 i 3 4 5 6 7 8 9 fuel is quickly depleted resulting in a drop in serum Daysofstarvation glucose levels figure 14 In order to make up for this loss of liver glycogen as an energy source the body39s metabolism changes in two important ways First flux through the gluconeogenic pathway in the liver and kidneys is increased to generate glucose for the brain and erythrocytes The major substrates for gluconeogenesis underthese conditions are glycerol alanine glutamate and lactate The glycerol comes from triacylglycerol hydrolysis in adipose tissue whereas alanine and lactate are produced by transamination reactions and anaerobic respiration M g Fatty acids Relative Change Glucose Liver glycogen Starvation 8 7 6 I Ketonebodies 4 v 39 3 2 744 Glucose Serum concentration mM H respeCtlvelyx In mUSCIe Mass Energy Survival cells Glutamate which is Tvpe of fuel Tissue kg Calories time the preferred 39I39riacylglycerols Adipose tissue 15 141000 83 days 39 Proteins Skeletal muscle 6 24000 I4 da 395 glugoneOgemc precursor Glycogen Skeletal muscle 015 600 84 liours In kldney cells39 IS an Glycogen Liver 007 300 42 hours abundant metabOIIte In Glucose fatty acids Circulatory system 0023 100 14 hours the blood that is triacylglyccmls deaminated to generate TUIUI 166000 Calories 98 days aketoglutarate a citrate Assuming I700 Calories da basal metabolism 11 of 14 pages Bioc 460 Dr Miesfeld Spring 2008 cycle intermediate that gives rise to the gluconeogenic intermediate oxaloacetate The second way our bodies cope with the depletion of liver glycogen is to switch most of the energy needs to using fatty acids as the primary metabolic fuel This spares whatever glucose is available for the brain and erythrocytes The fatty acids used as metabolic fuel during starvation are derived from triacylglycerol hydrolysis in the adipose tissue following glucagon stimulation of protein kinase Amediated signaling As shown above in figure 15 an average size man of 70 Kg contains enough metabolic fuel to live 98 days without food assuming a minimum energy expenditure of 1700 Calories per day 1660001700 976 By far the bulk of stored metabolic fuel is in the form of triacylglycerols in adipose tissue which is sufficient to prolong life for 3 months Protein is the second most abundant stored fuel 14 days worth of energy but as described earlier metabolic adaptations to starvation Figure 16 HEART BRAIN ATP Glucose K39DNEV co2 H20 4 AcetthoA P imam t y ATP pymvate l Oxaloacetateaalumse t AcetyKoA 02 H10 V Glucose f arketoglutarate Fatty acid NH4 gt o Excrered Urea Ammo adds L39VER ADIPOSE Glucose Urea T 1 saw WWW gtAce yICoA DHAP 1 Fatty acid Triacyglycerul Lacme t Fatty acid GlycfrolsP Glycerol Glycerol Glycerol lt SKELETAL MUSCLE Lactate Fatty acid Amino T l acids T l Pyruvate WWW T C02 H20 Protein ATP 12 of14 pages Bioc 460 Dr Miesfeld Spring 2008 ensure that this form ofenergy is spared for as long as possible Interestingly an obese individual with three times as much body fat as a normal person could theoretically survive starvation for up to eight months 249 days However as discussed in the next section chronic obesity a disease state that has reached epidemic proportions in the United States actually shortens life span due to an increase incidence of type 2 diabetes and cardiovascular disease Metabolite flux between major tissues and organs in the human body under starvation conditions is illustrated in gure 16 Once glycogen stores are depleted rst 24 hours adipose tissue and skeletal muscle are the primary sources of metabolic fuel during starvation Fatty acids released from triacylglycerol hydrolysis in adipose tissue are transported to skeletal muscle and the heart by serum albumin protein and used to generate acetylCoA for the citrate cycle and oxidative phosphorylation AcetylCoA produced from fatty acids transported to the liver is used the production of ketone bodies that are an important energy source forthe heart and brain during starvation Amino acids derived from protein degradation in skeletal muscle provides the necessary carbon from gluconeogenic amino acids and lactate to produce glucose in liver cells by gluconeogenesis Amino acids are also used by kidney cells for gluconeogenesis Glucose produced by gluconeogenesis is used by the brain and erythrocytes for aerobic and anaerobic respiration respectively The four major alterations in metabolic flux that permit humans to survive long periods of time without food can be summarized as follows 1 Increased triacylglycerol hydrolysis in adipose tissue Following depletion of liver glycogen within the rst 1224 hours of starvation triacylglycerol hydrolysis is stimulated in adipose tissue resulting in fatty acid and glycerol release into the blood Moreover glucose uptake by skeletal muscle is inhibited due to the low levels of insulin in the blood This has the effect of shifting energy away from glucose utilization and toward fatty acid oxidation for most tissues 2 Increased gluconeogenesis in liver and kidney cells In order to keep serum glucose levels above 35 mM which is needed for brain and erythrocyte functions ux through the gluconeogenic pathway is increased in liver and kidney cells The major substrates for glucose biosynthesis in the liver are glycerol alanine and lactate which are all converted to pyruvate Kidney cells primarily use glutamate from the blood to generate oxaloacetate 3 Increased ketogenesis in liver cells As a result of high rates of fatty acid oxidation and decreased amounts of oxaloacetate which is redirected toward gluconeogenesis acetyl CoA levels in the liver increase dramatically This leads to high levels of ketogenesis which produces acetoacetate and Dshydroxybutyrate for export to other tissues Under these conditions the brain and heart can use signi cant amounts of ketone bodies as a source of acetylCoA for aerobic respiration In contrast erythrocytes are totally dependent on glucose for glycolysis because they lack mitochondria which are required to oxidize acetyl CoA by the citrate cycle 4 Protein degradation in skeletal muscle tissue Muscle protein provides amino acids that serve as gluconeogenic substrates in the liver and kidneys While this is a good source of energy reserves from a storage point of view catabolism of skeletal muscle is delayed as long as possible to maintain mobility and enable the ongoing search for food Once protein stores fall below 50 of prestarvation levels life can no longer be sustained 13 of 14 pages Bioc 460 Dr Miesfeld Spring 2008 ANSWER To KEY QUESTION IN METABOLIC INTEGRATION The pancreas liver skeletal muscle and adipose tissue each play distinctive roles in maintaining serum glucose levels in our bodies at 45mM The pancreas is an endocrine organ that produces insulin and glucagon the two major peptide hormones involved in serum glucose regulation Insulin and glucagon are synthesized in a region ofthe pancreas called the islet of Langerhans with the 5 cells secreting insulin and the or cells secreting glucagon Insulin signaling stimulates glucose uptake primarily into liver skeletal muscle and adipose tissue in response to elevated serum glucose levels In liver cells the glucose is used for glycogen synthesis or it is converted to acetyICoA which is a substrate for fatty acid synthesis In contrast glucagon secretion from the pancreas promotes glucose ef ux from liver cells by activating glycogen degradation and gluconeogenesis The major role of skeletal muscle in regulating serum glucose levels is to remove excess glucose from the blood in response to insulin signaling Skeletal muscle tissue constitutes a large fraction of body mass and it is where the majority of glycogen in our bodies is stored Since muscle cells lack the enzymes glucose6 phosphatase and fatty acid synthase once glucose enters the muscle cell it cannot be exported to other tissues as an energy source Lastly adipose tissue uses glucose to synthesis glycerol for triacylglycerol production but it also affects glucose homeostasis indirectly by being the storage depot for fatty acids that are synthesized in the liver from excess carbohydrates obtained in the diet 14 of 14 pages
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