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MAMMAMALIAN METABOLISM. Integration and Hormonal Regulation. Objective. Consider the major metabolic pathways in the context of the whole organism. Issues with multicellular organism. Division of labor: cell differentiation Organ/Organ system specialization :

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Mammamalian metabolism

MAMMAMALIAN METABOLISM

Integration and Hormonal Regulation


Objective
Objective

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


Issues with multicellular organism
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


Approach
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



Glycolysis
Glycolysis

  • Metabolic degradation of glucose

    • Glucose is oxidized to:

      • 2 molecules of pyruvate

      • 2 molecules of ATP

      • 2 molecules of NADH


Anaerobic conditions
Anaerobic Conditions

  • Pyruvate converted into Lactate

    • Requires oxidation of NADH

    • Recycles NADH

  • In yeast:

    • Pyruvate converted into ethanol


Aerobic conditions
Aerobic Conditions

  • Glycolysis first step for further oxidationof glucose

  • NADH is processed through Oxidative Phosphorylation

    • Regenerates oxidized NAD

    • Generates ATP


Regulation of glycolysis
Regulation of glycolysis

  • Phosphofructokinase (PFK)

    • Activated by:

      • Increase in AMP, ADP

      • Fructose 2,6-bisphosphate

    • Inhibited by:

      • Increase in ATP

      • Citrate


Regulation of glycolysis1
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


Gluconeogenesis
Gluconeogenesis

  • Synthesis of glucose from simplier, noncarbohydrate precusor

    • Pyruvate

    • Lactate

    • Oxaloacetate

    • Glycerol

    • Gluconeogenic amino acids


Gluconeogenesis1
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


Gluconeogenesis2
Gluconeogenesis

  • Reciprical regulation of PFK and FBPase

    • Regulates rate and direction through glycolysis and gluconeogenesis

    • Both may be active simultaneously


Glycogen degradation and synthesis
Glycogen: degradationand 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


Fatty acid degradation and synthesis
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


Fatty acid degradation and synthesis1
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


Citric acid cycle
Citric Acid Cycle

  • Acetyl CoA oxidized to:

    • CO2

    • H20

  • Concomitant production of:

    • NADH

    • FADH2

  • Glycogenic Amino Acids

    • Enter at a cycle intermediate


Citric acid cycle1
Citric Acid Cycle

  • Regulatory enzymes

    • Citrate synthase

    • Isocitrate dehydrogenase

    • Alpha-ketoglutarate dehydrogenase

  • Controlled by:

    • Substrate availability

    • Feedback inhibition


Oxidative phosphorylation
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]


Pentose phosphate pathway
Pentose phosphate Pathway

  • Generates from G6P:

    • Ribose 5-phosphate

    • NADPH

  • Catalyzed by:

    • Glucose 6-phosphate dehydrogenase

  • Regulated by:

    • [NADP+]

  • NADPH is needed for biosynthesis


Amino acid degradation and synthesis
Amino Acid:degradationand synthesis

  • Excess AA:

    • Degraded to common metabolic intermediates

    • Most paths

      • Begin with transamination to alpha-keto acid

      • Eventually amino group transferred to urea


Amino acid degradation and synthesis1
Amino Acid:degradationand 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


Amino acid degradation and synthesis2
Amino Acid:degradationand synthesis

  • Glucogenic AA

    • Converted into glucose precursors

    • Precursors:

      • Pyruvate

      • Oxaloacetate

      • Alpha-ketoglutarate

      • Succinyl CoA

      • fumarate


Amino acid degradation and synthesis3
Amino Acid:degradationand 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


Two key compounds
Two Key Compounds

  • Acetyl-CoA, pyruvate

  • At metabolic crossroads


Acetyl coa
Acetyl-CoA

  • Degradation products of most fuels

  • Oxidized to CO2 and H2O in citric acid cycle

  • Can be used to synthesize FA


Pyruvate
Pyruvate

  • Product of:

    • Glycolysis

    • Dehyddrogenation of lactate

    • Some glucogenic AA

  • Can yield acetyl-CoA

    • Enter CAC

    • Biosynthesis of FA


Pyruvate1
Pyruvate

  • Carboxylated via pyruvate carboxylase

    • Forms oxaloacetate

      • Replenishes intermediates

      • Gluconeogenesis

        • Via phosphoenolpyruvate

        • Bypass of irreversible step in glycolysis

    • Precursor to several AA


Sites
Sites

  • Cytosolic:

    • Glycolysis

    • Glycogen synthesis, degradation

    • FA synthesis

    • Pentose Phosphate pathway


Sites1
Sites

  • Mitochondrial:

    • FA degradation

    • Citric Acid cycle

    • Oxidative Phosphorylation


Sites2
Sites

  • Both:

    • Gluconeogenesis

    • AA degradation

  • Location controlled by specific membrane transporters

    • Esp. inner mitochondrial membrane

    • Controls flow of metabolites


Regulation
Regulation

  • Intercellular Regulating Mechanisms

    • Hormones

    • Trigger cellular response

      • Short-term: second messenger

      • Long-term: protein synthesis

  • Molecular Level

    • Feedback

    • Substrate availability



Tsm liver
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


Tsm liver1
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


Sugars
Sugars

  • Role as Blood glucose “Buffer”

    • Absorbs and releases glucose

      • Response to levels of:

        • Glucagon

        • Epinepherine

        • Insulin

      • Response to [glucose]


Glucose absorption
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]


Glucose absorption1
Glucose absorption

  • Other monosaccarides

    • Can be converted to G6P

    • Includes

      • Fructose

      • Galactose

      • Mannose


Release of glucose
Release of glucose

  • No food

    • Blood glucose levels drop

    • Liver keeps blood glucose at about 4mM


Fate of glucose
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


Fate of glucose1
Fate of glucose

  • G6P to acetyl-CoA

    • By glycolysis

    • Need pyruvate dehydrogenase

    • Used for synthesis of

      • FA

      • Phospholipids

      • Cholesterol to bile acids


Fate of glucose2
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


Fate of fatty acids
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


Fate of fatty acids1
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


Fa degradation and synthesis
FA: degradationand synthesis

  • Compartmentalized

    • Prevent futile cycling

    • FA oxidation: in mitochondria

    • FA synthesis: in cytosol


Fa degradation and synthesis1
FA: degradationand 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


Fa degradation and synthesis2
FA: degradationand 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


Fatty acids
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


Fate of amino acids
Fate of Amino Acids

  • AA degraded to variety of intermediates

    • Glucogenic AA

      • Pyruvate

      • Citric acid intermediates

    • Ketogenic AA

      • Ketone bodies (sometimes)


Fate of amino acids1
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


Fate of amino acids2
Fate of Amino Acids

  • AA degraded to variety of intermediates

    • Glucogenic AA

      • Pyruvate

      • Citric acid intermediates

    • Ketogenic AA

      • Ketone bodies (sometimes)


Tsm brain
TSM: Brain

  • High Respiratory Rate

    • About 2% of body weight; 20% of resting O2 consumption

    • Independent of activity level

    • Most: power (Na+-K+)-ATPase


Tsm brain1
TSM: Brain

  • Most conditions

    • Only fuel: glucose

    • Extended fasting: ketone body

    • Needs steady suppy


Tsm brain2
TSM: Brain

  • With blood glucose below half normal

    • Brain dysfunction

    • Drop more

      • Coma

      • Irreversible damage

      • death


Tsm muscle
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


Tsm muscle1
TSM: Muscle

  • Energy Reservoir

    • Proteins into Amino Acids

    • Amino Acids into Pyruvate

    • Pyruvate into Alanine into the liver into pyruvate into glucose


Epinephrine receptors
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


Muscle contraction
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


Muscle fatigue
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


Muscle fatigue1
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


Cause of fatigue
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


Tsm cardiac muscle
TSM: Cardiac Muscle

  • Continuous activity

  • Aerobic

    • Many mitochondria

  • Fuel

    • FA: fuel of choice

    • Ketone bodies

    • Stored glycogen to glucose (with heavy workload)

    • Pyruvate

    • lacctate


Tsm adipose tissue adipocytes
TSM: Adipose Tissue/Adipocytes

  • General Metabolism

    • Location

      • Under skin

      • Abdominal cavity

      • In skeletal muscle

      • Around blood vessels

      • In mammary glands


Tsm adipose tissue adipocytes1
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)


Tsm adipose tissue adipocytes2
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


Tsm adipose tissue adipocytes3
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


Tsm adipose tissue adipocytes4
TSM: Adipose Tissue/Adipocytes

  • Rate of Glucose uptake by adipocytes

    • Regulated by:

      • Insulin

      • Glucose availability

    • Controlling factor in

      • Formation of triglycerides

      • Mobilization of triglycerides


Tsm blood
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)


Tsm blood1
TSM: Blood

  • Composition

    • About 5-6L in average adult

    • Cells/formed elements

      • Erythrocytes

      • Leukocytes

      • Platelets


Tsm blood2
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