overview of metabolism & the provision of metabolic fuels [chp 16 harper] -tjl

OVERVIEW OF METABOLISM & THE PROVISION OF METABOLIC FUELS [CHP 16 HARPER]TJLam MD2014B

BIOMEDICAL IMPORTANCEMetabolism

- the interconversion of chem’l compounds in the body, the pathways taken by individual molecules, their interrelationships, and mechanisms that regulate the flow of metabolites through the pathways

- [normal metabolism] adaptation to periods of starvation, exercise, pregnancy, and lactation

3 categories:Anabolic pathway

- Synthesis of larger/more complex compounds from smaller precursors

- Endothermic

Catabolic pathway - Breakdown of larger molecules; degradation- Oxidative reactions- Exothermic- Produce reducing equivalents & ATP [via respi chain]

Amphibolic pathway- "crossroads" of metabolism, acting as links between

the anabolic and catabolic pathways- E.g. CAC, ETC

Animals energy req’t:↑ size = ↓ energy req’t/kg body wt↓ size = ↑ energy req’t/kg body wt*growing children and animals have a proportionally higher requirement to allow for the energy cost of growth

Energy req’t met for human beings:- CHO [40-60%]- CHON [10-15%]- Fats, mainly triacylglycerol [30-40%]- Alcohol

*Ave physical activity ↑ metabolic rate by 40-50% over BMR

Obesity- If intake of metabolic fuel consistently ↑ than energy

expenditure, surplus stored largely as TG in adipose tissue

Emanciation- If intake consistently ↓ than expenditure, there are

negligible reserves of fat and carbohydrate, & AA arising from protein turnover are used for energy-yielding metabolism rather than replacement protein synthesis

Fed State- For several hours after a meal, while the products of

digestion are being absorbed- Ample supply of carbohydrate/metabolic fuels

Fasting state- Glucose spared for CNS & RBC

o CNS – largely dependent on glucoseo RBC – wholly dependent on glucose

- Muscles & liver oxidize FA- Liver synthesizes ketones from FA to export to

muscles/tissuesAs Glycogen ↓; AA from CHON turnover are used for gluconeogenesis [process of forming glucose from noncarbohydrate precursors]

Insulin & Glucagon- Largely controls the formation & utilization of

reserves of TG & glycogen & extent to w/c glucose is taken-up & oxidized

PATHWAYS OF THE MAJOR PRODUCTS OF DIGESTION- In ruminants, dietary cellulose is fermented by

symbiotic microorganisms to short-chain FA (acetic, propionic, butyric), and metabolism in these animals is adapted to use these FA as major substrates

- All the products of digestion are metabolized to a common product, acetyl-CoA, which is then oxidized by the CAC

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GLUCOSE METABOLISM- Glucose is the major fuel of most tissues. It is

metabolized to pyruvate by the pathway of glycolysis. Aerobic tissues metabolize pyruvate to acetyl-CoA, w/c can enter the CAC for complete oxidation to CO2 and H2O, linked to the formation of ATP in the process of oxidative phosphorylation

- Glycolysis can also occur anaerobically when the end product is lactate

Glucose and its metabolites also take part in other processes:1. Synthesis of the storage polymer glycogen in skeletal

muscle and liver2. The pentose phosphate pathway, an alternative to

part of the pathway of glycolysiso source of reducing equivalents (NADPH) for

fatty acid synthesis

o source of ribose for nucleotide and nucleic acid synthesis

3. Triose phosphates → glycerol moiety of TG4. Pyruvate and intermediates of the CAC provide the

carbon skeletons for the synthesis of AA, and acetyl-CoA is the precursor of fatty acids and cholesterol (and hence of all steroids synthesized in the body)

LIPID METABOLISM- The source of long-chain FA is either dietary lipid or - de novo synthesis

o carbohydrate or amino acids → acetyl-CoA- β-oxidation

o Fatty acids oxidized to acetyl-CoA- Esterification

o FA esterified with glycerol → triacylglycerol [body's main fuel reserve]

Acetyl-CoA formed by -oxidation may undergo three fates:1. As with acetyl-CoA arising from glycolysis, it is

oxidized to CO2 + H2O via the citric acid cycle2. It is the precursor for synthesis of long chain FA,

cholesterol and other steroids3. In the liver, it is used to form ketone bodies

(acetoacetate and 3-hydroxybutyrate) that are important fuels in prolonged fasting

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AMINO ACID METABOLISMEssential amino acids

- since they cannot be synthesized in the bodyNonessential amino acidssupplied in the diet, but can also be formed from metabolic intermediates by transamination using the amino nitrogen from other amino acids

After deamination, amino nitrogen is excreted as urea, and the carbon skeletons that remain after transamination may:

1. be oxidized to CO2 via the citric acid cycle2. be used to synthesize glucose (gluconeogenesis)3. form ketone bodies, which may be oxidized or be

used for synthesis of fatty acids

METABOLIC PATHWAYS AT TISSUE/ORGAN LEVELHepatic Portal Vein

- where AA from the digestion of dietary CHON and glucose from the digestion of CHO are absorbed

Liver- has the role of regulating the blood concentration of

water-soluble metaboliteso Glycogenesis = glucose → glycogeno Lipogenesis = glucose → FAo Glycogenolysis = glycogen → glucoseo Gluconeogenesis = non-CHO → glucose

[together w/ kidneys]- synthesizes the major plasma proteins [albumin]- deaminates AA that are in excess of req’ts, forming

urea, w/c is excreted by kidneys

Skeletal muscle- accounts for approximately 50% of body mass- represents a considerable store of protein that can

be drawn upon to supply amino acids for gluconeogenesis in starvation

- utilizes glucose as a fuelo aerobically, forming CO2

o anaerobically, forming lactateLipids

- hydrolyzed to monoacylglycerols and FA in the gut, then re-esterified in the intestinal mucosa

o here they are packaged with protein and secreted into the lymphatic system and thence into the bloodstream as chylomicrons TG

*major source of long-chain FA is synthesis from CHO, in adipose tissue and the liver

- in the liver, TG arising from lipogenesis, free FA, and chylomicron remnants is secreted into the circulation in very low density lipoprotein (VLDL)

*TG undergoes a fate similar to that of chylomicronsChylomicrons

- Largest of plasma lipoproteins- Also contain other lipid-soluble nutrients- is not taken up directly by the liver, It is first

metabolized by tissues that have lipoprotein lipase, which hydrolyzes the TG, releasing FA that are incorporated into tissue lipids or oxidized as fuel

*chylomicron remnants are cleared by the liver

Lipolysis- TG hydrolyzed into glycerol & free FA w/c are

released into circulationo Glycerol – substrate for gluconeogenesiso FA transported bound to serum albumin;

they are taken up by most tissues (but not brain or erythrocytes) and either esterified to TG for storage or oxidized as a fuel

Ketogenesis- Partial oxidation of fatty acids in the liver leads to

ketone body production- Ketone bodies are transported to extrahepatic

tissues, where they act as a fuel in prolonged fasting and starvation

METABOLIC PATHWAYS AT SUBCELLULAR LEVEL- Compartmentation of pathways in separate

subcellular compartments or organelles permits integration and regulation of metabolism

Central role of Mitochondrion:1. Citric acid cycle2. Β-oxidation of FA3. Ketogenesis4. Respiratory chain5. ATP synthase

Cytosol:1. Glycolysis2. Pentose Phosphate Pathway3. FA synthesis

*In gluconeogenesis, substrates such as lactate and pyruvate, which are formed in the cytosol, enter the mitochondrion to yield oxaloacetate as a precursor for the synthesis of glucose in the cytosol

Endoplasmic Reticulum - contain the enzyme system for triacylglycerol

synthesisRibosomes

- responsible for protein synthesis of 7


THE FLUX OF METABOLITES- Regulation of the overall flux through a pathway is

important to ensure an appropriate supply of the products of that pathway

- achieved by control of one or more key reactions in the pathway, catalyzed by regulatory enzymes

- The physicochemical factors that control the rate of an enzyme-catalyzed reaction, such as substrate concentration, are of primary importance in the control of the overall rate of a metabolic pathway

Reaction at equilibrium- forward and reverse reactions occur at equal rates- no net flux in either direction

In vivo, under "steady-state" conditions- there is a net flux from left to right- there is a continuous supply of A and removal of D

- there are invariably one or more nonequilibrium reactions in a metabolic pathway

Reactions at Nonequilibrium- the reactants are present in concentrations that are

far from equilibrium- In attempting to reach equilibrium, large losses of

free energy occur, making this type of reaction essentially irreversible

- Such a pathway has both flow and direction- enzymes catalyzing nonequilibrium reactions are

usually present in low concentration and are subject to a variety of regulatory mechanisms

*most reactions in metabolic pathways cannot be classified as equilibrium or nonequilibrium, but fall somewhere between the two extremes

Flux-Generating Reaction- 1st reaction in a pathway that is saturated with

substrate- a nonequilibrium reaction in which the Km of the

enzyme is considerably lower than the normal substrate concentration

ALLOSTERIC & HORMONAL MECHANISMS- A↔B and C↔D are equilibrium reactions and B→C

is a nonequilibrium reaction- The flux through such a pathway can be regulated by

the availability of substrate A.

- Flux is also determined by removal of the end product D and the availability of cosubstrates or cofactors represented by X and Y

- Enzymes catalyzing nonequilibrium rxns are often allosteric CHONs subject to the rapid actions of "feed-back" / "feed-forward" control by allosteric modifiers, in immediate response to needs of the cell

o product of a biosynthetic pathway inhibits the enzyme catalyzing the first reaction in the pathway

- Other control mechanisms depend on the action of hormones responding to the needs of the body as a whole

o they may act rapidly by altering the activity of existing enzyme molecules

o or slowly by altering the rate of enzyme synthesis

MANY METABOLIC FUELS ARE INTERCONVERTIBLECarbohydrates

- CHON in excess of rq’ts for energy & formation of glycogen in muscle and liver can readily be used for synthesis of FA, and hence TG in both adipose tissue and liver [exported in VLDL]

- Western countries dietary fat provides 35–45% of energy intake

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- In less-developed countries, carbohydrate may provide 60–75% of energy intake

- A high intake of fat inhibits lipogenesis in adipose tissue and liver

Fatty Acids- Fatty acids (and ketone bodies formed from them)

cannot be used for the synthesis of glucose- The reaction of pyruvate dehydrogenase, forming

acetyl-CoA, is irreversible, and for every two-carbon unit from acetyl-CoA that enters the citric acid cycle, there is a loss of two carbon atoms as carbon dioxide before oxaloacetate is reformed

o acetyl-CoA (+ any substrates yielding acetyl-CoA) can never be used for gluconeogenesis

- The (relatively rare) fatty acids with an odd number of carbon atoms yield propionyl CoA as the product of the final cycle of oxidation, and this can be a substrate for gluconeogenesis, as can the glycerol released by lipolysis of adipose tissue triacylglycerol reserves.

Amino Acids- Most of the AAs in excess of rq’ts for CHON synthesis

yield pyruvate, or four- and five-carbon intermediates of the citric acid cycle

Glucogenic Amino Acids- The most glucogenic: Alanine- Pyruvate [primary substrate] and the other

intermediates of CAC that results in a net increase of the formation of oxaloacetate [for gluconeogenesis]

o Lysine & Leucine yield only acetyl-CoA on oxidation,

and hence cannot be used for gluconeogenesis

o Phenylalanine, Tyrosine, Tryptophan, & Isoleucine

give rise to both acetyl-CoA and intermediates that can be used for gluconeogenesis

Ketogenic AAs- Those amino acids that give rise to acetyl-CoA

o because in prolonged fasting and starvation much of the acetyl-CoA is used for synthesis of ketone bodies in the liver

SUPPLY OF METABOLIC FUELSErythrocytes [RBCs]

- lacks mitochondria, hence wholly reliant on glycolysis and PPP [aerobic]

CNS [Brain]- can metabolize ketone bodies to meet about 20% of

its energy requirements - [80% glucose]

* fetus requires a significant amount of glucose, as does the synthesis of lactose in lactationFED STATE: METABOLIC FUELS ARE LAID DOWN

- glucose is the major fuel for oxidation in most tissues; observed as an increase in the respiratory quotient (the ratio of carbon dioxide produced/oxygen consumed) from about 0.8 in the fasting state to near 1

Oxidation of Metabolic Fuels

Energy Yield (kJ/g)

O2

Consumed (L/g)

CO2

Produced (L/g)

RQ (CO2

Produced/O2

Consumed)

Energy (kJ)/L O2

CHO 16 0.829 0.829 1.00 20

CHON 17 0.966 0.782 0.81 20

Fat 37 2.016 1.427 0.71 20

Alcohol 29 1.429 0.966 0.66 20

INSULIN- controls glucose uptake into muscle and adipose

tissue- secreted by the β-islet cells of the pancreas in

response to an increased concentration of glucose in the portal blood

- In Fasting State, glucose transporter of muscle and adipose tissue (GLUT-4) is in intracellular vesicles

o early response to insulin is the migration of vesicles to the cell surface, where they fuse with the plasma membrane, exposing active glucose transporters [↑glucose uptake]

o As insulin secretion falls in the fasting state, so the receptors are internalized again, reducing glucose uptake

In the Liver- Glucose uptake is independent of insulin- has an isoenzyme of hexokinase (glucokinase) with a

high K m, so that as the concentration of glucose entering the liver increases, so does the rate of synthesis of glucose 6-phosphate

- Is in excess of the liver's rq’t for energy-yielding metabolism, and is used mainly for glycogenesis

In both liver and skeletal muscle- insulin stimulates glycogen synthetase- inhibit glycogen phosphorylase- Some of the add’l glucose entering liver may be used

for lipogenesis and hence triacylglycerol synthesis

In adipose tissue- ↑ insulin stimulates glucose uptake, its conversion to

fatty acids and their esterification to triacylglycerol

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o It inhibits intracellular lipolysis and release of FFA.

PRODUCTS OF LIPID DIGESTIONIn adipose tissue and skeletal muscle

- extracellular lipoprotein lipase is synthesized and activated in response to insulin

o the resultant nonesterified fatty acids are largely taken up by the tissue and used for synthesis of triacylglycerol

o the glycerol remains in the bloodstream → the liver and used for either gluconeogenesis and glycogen synthesis or lipogenesis

In the liver- Fatty acids remaining in the bloodstream are taken

up by the liver and reesterified- lipid-depleted chylomicron remnants are cleared by

the liver, and the remaining TG is exported, together with that synthesized in the liver, in VLDL

PROTEIN- Under normal conditions, CHON catabolism is more

or less constant throughout the day- only in cachexia associated with advanced cancer

and other diseases → ↑ rate of CHON catabolism- The ↑rate of CHON synthesis in response to

↑availability of AAs and metabolic fuel is again a response to insulin action

- CHON synthesis is an energy expensive process; it may account for up to 20% of resting energy expenditure after a meal, but only 9% in fasting state

FASTING STATE: METABOLIC FUELS ARE MOBILIZED- glucose may represent less than 10% of whole body

energy-yielding metabolism

Plasma Concentrations of Metabolic Fuels (mmol/L)

Fed 40 Hours Fasting

7 Days Starvation

Glucose 5.5 3.6 3.5

Free fatty acids 0.30 1.15 1.19

Ketone bodies Negligible 2.9 4.5

Glucagon- Secreted by the α cells of the pancreas- inhibits glycogen synthetase- activates glycogen phosphorylase in the liver & is

hydrolyzed by glucose 6-phosphatase → glucose is released into the blood for use by the CNS and RBC

In muscles

- glycogen cannot contribute directly to plasma glucose bc. lacks glucose 6-phosphatase

- 1° purpose of muscle glycogen is to provide a source of glucose 6-phosphate for its own energy

- acetyl-CoAo formed by oxidation of FA in muscleo inhibits pyruvate dehydrogenase →

accumulation of pyruvateo transaminated to alanine, at the expense of

AAs arising from breakdown of "labile" protein reserves synthesized in the fed state. Alanine & keto acids resulting from transamination are exported from muscle, and taken up by the liver, where the alanine is transaminated to yield pyruvate

o The resultant AAs are largely exported back to muscle, to provide amino groups for formation of more alanine, while the pyruvate is a major substrate for gluconeogenesis in the liver

In Adipose Tissue- ↓ insulin & ↑ in glucagon results in inhibition of

lipogenesis, inactivation of lipoprotein lipase, and activation of intracellular hormone-sensitive lipase

o leads to release from ↑ amounts of glycerol (substrate for gluconeogenesis in the liver) and FFAs, w/c are used by liver, heart, and skeletal muscle as their preferred metabolic fuel, therefore sparing glucose.

CLINICAL ASPECT- prolonged fasting → ↑AAs released as a result of

protein catabolism – for gluconeogenesis & metabolic fuel

- prlonged fasting & cachexia [due to cytokines] essential tissue proteins catabolized & not replaced → Death

- high demand for glucose by the fetus, and for lactose synthesis in lactation, can lead to ketosis

- Type 1 DMo ↑ gluconeogenesis from AAs in livero ↑ lipolysis in adipose tissue, and the

resultant FFAs are substrates for ketogenesis in the liver

o Lack of oxaloacetate → impaired utilization of ketone bodies

o acetoacetate and 3-hydroxybutyrate are strong acids → Acidosis

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o Coma results from both the acidosis and ↑ osmolality of extracellular fluid (result of the hyperglycemia)

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overview of metabolism & the provision of metabolic fuels [chp 16 harper] -tjl

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