MAMMAMALIAN METABOLISM

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MAMMAMALIAN METABOLISM

• Integration and Hormonal Regulation

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Objective

• Consider the major metabolic pathways in the
  context of the whole organism

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Issues with multicellular organism

• Division of labor cell differentiation
• Organ/Organ system specialization
• Characteristic fuel requirements
• Characteristic metabolic patterns
• Hormone Regulation
• Integrate/coordinate metabolic functions of
  different tissue
• Maximize fuel/fuel precursor allocations to each
  organ

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Approach

• Recapitulate major pathways and control systems
• Consider how these processes are divided among
  tissues and organs
• Consider major hormones that control these
  metabolic functions

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Major pathways and Strategies of energy metabolism
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Glycolysis

• Metabolic degradation of glucose
• Glucose is oxidized to
• 2 molecules of pyruvate
• 2 molecules of ATP
• 2 molecules of NADH

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Anaerobic Conditions

• Pyruvate converted into Lactate
• Requires oxidation of NADH
• Recycles NADH
• In yeast
• Pyruvate converted into ethanol

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Aerobic Conditions

• Glycolysis first step for further oxidationof
  glucose
• NADH is processed through Oxidative
  Phosphorylation
• Regenerates oxidized NAD
• Generates ATP

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Regulation of glycolysis

• Phosphofructokinase (PFK)
• Activated by
• Increase in AMP, ADP
• Fructose 2,6-bisphosphate
• Inhibited by
• Increase in ATP
• Citrate

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Regulation of glycolysis

• Fructose 2,6-bisphosphate (F2,6P)
• Influenced by cAMP
• Liver
• Increase cAmp, decrease F2,6P
• Muscle
• Increase cAmp, increase F2,6P
• Mediated by
• glucogon
• Epinephrine
• norepinephrine

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Gluconeogenesis

• Synthesis of glucose from simplier,
  noncarbohydrate precusor
• Pyruvate
• Lactate
• Oxaloacetate
• Glycerol
• Gluconeogenic amino acids

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Gluconeogenesis

• Mainly through pathways in the liver
• Major intermediate oxaloacetate
• Converted to phospoenolpyruvate
• Then, into glucose
• Irreversible Steps
• PFK bypass Fructose 1,6-bisphosphatase
• Hexokinase bypass glucose 6-phosphatase

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Gluconeogenesis

• Reciprical regulation of PFK and FBPase
• Regulates rate and direction through glycolysis
  and gluconeogenesis
• Both may be active simultaneously

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Glycogen degradation and synthesis

• Storage form of glucose in most animals
• In liver and muscle
• Enters glycolysis
• Catalyzed by glycogen phosphorylase
• Converted into glucose 6-phosphate (G6P)
• Opposed by glycogen synthase
• Enzymes respond to
• Glucagon
• epinephrine

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Fatty Acid Degradation and Synthesis

• Degradation beta-oxidation
• In 2 carbon chunks
• Form acetyl-CoA
• Regulated by FA
• Lipase in adipose cells hormone sensitive
• cAMP mediated
• Stimulated by
• Glucogon
• Epinephrine
• Inhibited by
• insulin

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Fatty Acid Degradation and Synthesis

• Synthesis from acetly CoA
• Acetyl-CoA carboxylase
• Activated by citrate
• Inhibited by intermediate (palmitoyl-CoA)
• Long term regulation
• Stimulated by insulin
• Inhibited by fasting

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Citric Acid Cycle

• Acetyl CoA oxidized to
• CO2
• H20
• Concomitant production of
• NADH
• FADH2
• Glycogenic Amino Acids
• Enter at a cycle intermediate

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Citric Acid Cycle

• Regulatory enzymes
• Citrate synthase
• Isocitrate dehydrogenase
• Alpha-ketoglutarate dehydrogenase
• Controlled by
• Substrate availability
• Feedback inhibition

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Oxidative Phosphorylation

• Major products
• NADH is oxidized to NAD
• FADH2 is oxidized to FAD
• Coupled to synthesis of ATP
• Rate dependent upon
• ATP
• ADP
• Pi

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Pentose phosphate Pathway

• Generates from G6P
• Ribose 5-phosphate
• NADPH
• Catalyzed by
• Glucose 6-phosphate dehydrogenase
• Regulated by
• NADP
• NADPH is needed for biosynthesis

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Amino Aciddegradation and synthesis

• Excess AA
• Degraded to common metabolic intermediates
• Most paths
• Begin with transamination to alpha-keto acid
• Eventually amino group transferred to urea

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Amino Aciddegradation and synthesis

• Ketogenic AA
• E.g. leucine, lysine, tryptophane,
  phenylalanine, tyrosine, isoleucine
• Only leucine, lysine exclusively ketogenic
• Converted into
• Acetyl-CoA
• Acetoacetyl-CoA
• Can not be glucose precursors

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Amino Aciddegradation and synthesis

• Glucogenic AA
• Converted into glucose precursors
• Precursors
• Pyruvate
• Oxaloacetate
• Alpha-ketoglutarate
• Succinyl CoA
• fumarate

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Amino Aciddegradation and synthesis

• Other situations
• 4 AA are both ketogenic and glucogenic
• Tryptophan,Phenylalanine,Tyrosine,Isoleucine
• Essential AA cannot be synthesized
• Histidine, Isoleucine, Leucine, Lysine,
  Methionine, Phenylalanine, Threonine, Tryptophan,
  Valine, and Arginine (in young)
• Nonessential AA can be synthesized

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Two Key Compounds

• Acetyl-CoA, pyruvate
• At metabolic crossroads

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Acetyl-CoA

• Degradation products of most fuels
• Oxidized to CO2 and H2O in citric acid cycle
• Can be used to synthesize FA

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Pyruvate

• Product of
• Glycolysis
• Dehyddrogenation of lactate
• Some glucogenic AA
• Can yield acetyl-CoA
• Enter CAC
• Biosynthesis of FA

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Pyruvate

• Carboxylated via pyruvate carboxylase
• Forms oxaloacetate
• Replenishes intermediates
• Gluconeogenesis
• Via phosphoenolpyruvate
• Bypass of irreversible step in glycolysis
• Precursor to several AA

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Sites

• Cytosolic
• Glycolysis
• Glycogen synthesis, degradation
• FA synthesis
• Pentose Phosphate pathway

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Sites

• Mitochondrial
• FA degradation
• Citric Acid cycle
• Oxidative Phosphorylation

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Sites

• Both
• Gluconeogenesis
• AA degradation
• Location controlled by specific membrane
  transporters
• Esp. inner mitochondrial membrane
• Controls flow of metabolites

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Regulation

• Intercellular Regulating Mechanisms
• Hormones
• Trigger cellular response
• Short-term second messenger
• Long-term protein synthesis
• Molecular Level
• Feedback
• Substrate availability

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Tissue Specific Metabolism
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TSM LIVER

• Liver central processing and distributing role
• Furnishes other tissues/organs with appropriate
  mix of nutrients via the blood
• Other tissues and organs are termed extrahepatic
  or peripheral
• Handles carbohydrates, amino acids and fats

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TSM LIVER

• Extremely adaptable to prevailing conditions
• Can shift enzymatic ally from one nutrient
  emphasis to another within hours
• Responds to the demands of extrahepatic
  tissues/organs for fuels
• Maintains blood levels of nutrients
• Well located for the task

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Sugars

• Role as Blood glucose Buffer
• Absorbs and releases glucose
• Response to levels of
• Glucagon
• Epinepherine
• Insulin
• Response to glucose

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Glucose absorption

• Hepatocytes are permeable to glucose
• Not insulin dependent
• Absorption driven by blood glucose
• Convert glucose to G6P
• Catalyzed by glucokinase (not hexokinase)
• Blood glucose
• Normally lower than max phosporylation rate of
  glucokinase
• Uptake about equal to blood glucose

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Glucose absorption

• Other monosaccarides
• Can be converted to G6P
• Includes
• Fructose
• Galactose
• Mannose

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Release of glucose

• No food
• Blood glucose levels drop
• Liver keeps blood glucose at about 4mM

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Fate of glucose

• Varies with metabolic requirement
• G6P to glucose
• Requires glucose 6-phosphatase
• Blood transport to peripheral organs
• G6P to glycogen
• When demand for glucose is low
• Glycogen to G6P
• When demand for glucose is low
• Signaled by increased
• Glucagon
• epinephrine

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Fate of glucose

• G6P to acetyl-CoA
• By glycolysis
• Need pyruvate dehydrogenase
• Used for synthesis of
• FA
• Phospholipids
• Cholesterol to bile acids

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Fate of glucose

• Substrate for the Pentose phosphate pathway
• NADPH needed for biosynthesis of
• Fatty acids
• Cholesterol
• D-ribose 5-phosphate
• precursor for nucleotide biosynthesis

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Fate of Fatty Acids

• Increased demand for metabolic fuel
• FA converted into acetyl-CoA into ketone bodies
• KB are transportable form of acetyl
• Exported via blood to tissues
• Up to one third of energy in heart
• 60-70 in brain during prolonged fast
• Major oxidative fuel of the liver
• FA converted into acetyl-CoA to CAC

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Fate of Fatty Acids

• Decreased demand for metabolic fuel
• FA converted into liver lipids
• Some acetyl from FA (and glucose) converted into
  cholesterol
• Specialized mechanisms for transport of lipids in
  blood
• Converted into lipoproteins, then to adipose for
  storage
• Bound to albumin as free FA, transported in blood
  to skeletal and cardiac muscle

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FA degradation and synthesis

• Compartmentalized
• Prevent futile cycling
• FA oxidation in mitochondria
• FA synthesis in cytosol

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FA degradation and synthesis

• Interactions
• Carnitine Palmitoly Transferase I (CPTI)
• Transport FA into mitochondria
• CPTI inhibited by Malonyl-CoA MCoA)
• MCoA is key intermediate in FA synthesis
• When FA are synthesized, can not transport FA
  into mitochondria

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FA degradation and synthesis

• Interactions
• When metabolic demand for fuel is low
• acetyl-CoA comes from glucose
• When metabolic demand for fuel is high
• Inhibits FA synthesis
• FA into Mitochondria into ketone bodies

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Fatty Acids

• Liver can not use Ketone Bodies
• Lacks 3-ketoacyl-CoA-transferase
• When metabolic demand is increased
• Fatty Acids are the liver's main source of
  acetyl-CoA

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Fate of Amino Acids

• AA degraded to variety of intermediates
• Glucogenic AA
• Pyruvate
• Citric acid intermediates
• Ketogenic AA
• Ketone bodies (sometimes)

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Fate of Amino Acids

• After about 6 hour fast
• Glycogen stores are depleted
• Gluconeogenesis from AA
• Mostly muscle protein
• Degrated to alanine and glutamine
• Animals can not convert Fat to Glucose
• Proteins are an important fuel reserve

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Fate of Amino Acids

• AA degraded to variety of intermediates
• Glucogenic AA
• Pyruvate
• Citric acid intermediates
• Ketogenic AA
• Ketone bodies (sometimes)

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TSM Brain

• High Respiratory Rate
• About 2 of body weight 20 of resting O2
  consumption
• Independent of activity level
• Most power (Na-K)-ATPase

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TSM Brain

• Most conditions
• Only fuel glucose
• Extended fasting ketone body
• Needs steady suppy

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TSM Brain

• With blood glucose below half normal
• Brain dysfunction
• Drop more
• Coma
• Irreversible damage
• death

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TSM Muscle

• Major Fuels
• Glucose from Glycogen
• FA
• Ketone Bodies
• Storage Glycogen
• Can Not Export Glucose
• No gluconeogenesis
• No G-6-phosphatase
• No receptors for Glucagon

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TSM Muscle

• Energy Reservoir
• Proteins into Amino Acids
• Amino Acids into Pyruvate
• Pyruvate into Alanine into the liver into
  pyruvate into glucose

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Epinephrine Receptors

• Regulates glycogen breakdown and synthesis
• Increase cAMP in muscle
• Activates glycogen breakdown
• Activates glycolysis
• Increase glucose consumption
• Epinephine acts independently of glycogen
• With insulin
• Regulates general blood glucose levels

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Muscle Contraction

• Skeletal Muscle at rest
• about 30 of O2 consumption
• Can increase 25 in exercise
• Shifts to glycolysis of G6P from glycogen
• Much of G6P into Lactate
• Cori Cycle
• Respiratory burden shifted to liver
• Delay of O2 dept

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Muscle Fatigue

• Definition
• Inability of muscle to maintain a given power
  output
• About 20 drop in contraction strength
• Aerobic ( Red Fiber slow twitch)
• Difficult to fatigue
• Oxidative Phosphorylation
• Good vascular supply
• myoglobin

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Muscle Fatigue

• Anaerobic
• With in about 20 sec in max exertion
• I.E. Tetanic Exertion
• Results from sustained contraction of white
  fibers (fast twitch)
• Depends on glycolysis
• Creatine phosphate (CP)
• Glygogen storage

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Cause of Fatigue

• Drop in intramuscular pH
• From 7.0 to as low a 6.4
• From glycolytic proton generation
• How does increased acidity cause muscle fatigue?
• Maybe decresed enzyme activity?
• Esp PFK

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TSM Cardiac Muscle

• Continuous activity
• Aerobic
• Many mitochondria
• Fuel
• FA fuel of choice
• Ketone bodies
• Stored glycogen to glucose (with heavy workload)
• Pyruvate
• lacctate

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TSM Adipose Tissue/Adipocytes

• General Metabolism
• Location
• Under skin
• Abdominal cavity
• In skeletal muscle
• Around blood vessels
• In mammary glands

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TSM Adipose Tissue/Adipocytes

• General Metabolism
• Quanity
• Normal male about 21
• Normal female about 25
• Functions
• Energy storage
• Maintenance of metabolic homeostasis (second only
  to the liver)

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TSM Adipose Tissue/Adipocytes

• General Metabolism
• Source of Fatty Acids
• Liver
• Diet
• To form stored triglycerides
• Fatty acyl-CoA esterified with PGA
• Glycerol-3-Phosphate
• Formed from reduction of DAP
• Glycolytically generated from glucose
• Adipose cells lack enzyme to phosphorylate
  endogenoous glycerol

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TSM Adipose Tissue/Adipocytes

• General Metabolism
• Hydrolyze triglycerides to Fatty Acids and
  Glycerol
• In response to levels of
• Glucogon
• Epinephrine
• Insulin
• Catalyzed by hormone-sensitive lipase
• Increased PGA reform triglycerides
• Decreased PGA release FA to blood

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TSM Adipose Tissue/Adipocytes

• Rate of Glucose uptake by adipocytes
• Regulated by
• Insulin
• Glucose availability
• Controlling factor in
• Formation of triglycerides
• Mobilization of triglycerides

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TSM Blood

• Mediates metabolism between organs
• Transports
• Nutrients
• Small intestine to liver
• Liver to adipose tissue, other organs
• Waste products
• Tissues to kidneys
• Respiratory gases
• O2 lungs to tissues
• CO2 tissues to lungs
• Regulatory molecules (hormones)

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TSM Blood

• Composition
• About 5-6L in average adult
• Cells/formed elements
• Erythrocytes
• Leukocytes
• Platelets

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TSM Blood

• Composition
• Plasma
• 90 water
• 10 solutes
• Plasma proteins
• Inorganic components
• Organic components
• Major effort of homeostasis to keep values within
  normal ranges
• Blood glucose levels are regulated by
• Epinephrine, glucagon and insulin

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