INTEGRATION OF METABOLISM

V.S.RAVIKIRAN, MSc.

V.S.RAVIKIRAN, MSc., Department of Biochemistry,

ASRAM Medical college, Eluru-534005.AP, India.vsravikiran2013@gmail.c

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Integration of Metabolism

1. Interconnection of pathways

2. Metabolic profile of organs

3. Food intake, starvation and obesity

4. Fuel choice during exercise

5. Ethanol alters energy metabolism

6. Hormonal regulation of metabolism

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Connection of Pathways

1. ATP is the universal currency of energy

2. ATP is generated by oxidation of glucose, fatty acids, and amino acids ; common intermediate -> acetyl CoA ; electron carrier -> NADH and FADH2

3. NADPH is major electron donor in reductive biosynthesis

4. Biomolecules are constructed from a small set of building blocks

5. Synthesis and degradation pathways almost always separated -> Compartmentation !!!

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Key Junctions between Pathways

How Is Metabolism Integrated in a Multicellular Organism?

• Organ systems in complex multicellular organisms have arisen to carry out specific physiological functions

• Such specialization depends on coordination of metabolic responsibilities among organs so that the organism as a whole can thrive

• Organs differ in the metabolic fuels they prefer as substrates for energy production (see Figure 27.7)

Figure 27.7 Metabolic relationships among the major human organs.

How Is Metabolism Integrated in a Multicellular Organism?

• The major fuel depots in animals are glycogen in liver and muscle; triacylglycerols in adipose tissue; and protein, mostly in skeletal muscle

• The usual order of preference for use of these is glycogen > triacylglycerol > protein

• The tissues of the body work together to maintain energy homeostasis

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Metabolic Profile of Organs

Brain

Brain has two remarkable metabolic features1. very high respiratory metabolism

20 % of oxygen consumed is used by the brain

2. but no fuel reservesUses only glucose as a fuel and is dependent on the blood for

a continuous incoming supply (120g per day)

In fasting conditions, brain can use -hydroxybutyrate (from fatty acids in liver), converting it to acetyl-CoA for the energy production via TCA cycle

Generate ATP to maintain the membrane potentials essential for transmission of nerve impulses

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Metabolic Profile of Brain

Glucose is fuel for human brain -> consumes 120g/day -> 60-70 % of utilization of glucose in starvation -> ketone bodies can replace glucose

Figure 27.8 Ketone bodies such as β-hydroxybutyrate provide the brain with a source of acetyl-CoA when glucose is unavailable.

Muscle• Skeletal muscles is responsible for about 30%

of the O2 consumed by the human body at rest• Muscle contraction occurs when a motor never

impulse causes Ca+2 release from endomembrane compartments

• Muscle can utilize a variety of fuels --glucose, fatty acids, and ketone bodies

• Rest muscle contains about 2% glycogen and 0.08% phoshpocreatine

Creatine Kinase in Muscle• About 4 seconds of exertion, phosphocreatine

provide enough ATP for contraction• During strenuous exertion, once

phosphocreatine is depleted, muscle relies solely on its glycogen reserves

• Glycolysis is capable of explosive bursts of activity, and the flux of glucose-6-P through glycolysis can increase 2000-fold almost instantaneously

• Glycolysis rapidly lowers pH (lactate accumulation), causing muscle fatigue

Creatine Kinase and Phosphocreatine Provide an Energy Reserve in Muscle

Figure 27.9 Phosphocreatine serves as a reservoir of ATP-synthesizing potential.

Muscle Protein Degradation

• During fasting or excessive activity, amino acids are degraded to pyruvate, which can be transaminated to alanine

• Alanine circulates to liver, where it is converted back to pyruvate – a substrate for gluconeogenesis

• This is a fuel of last resort for the fasting or exhausted organism

Figure 27.10 The transamination of pyruvate to alanine by glutamate:alanine aminotransferase.

Heart

• The activity of heart muscle is constant and rhythmic

• The heart functions as a completely aerobic organ and is very rich in mitochondria

• Prefers fatty acid as fuel• Continually nourished with oxygen and free

fatty acid, glucose, or ketone bodies as fuel

Adipose tissue• Amorphous tissue widely distributed about

the body• Consist of adipocytes• ~65% of the weight of adipose tissue is

triacylglycerol• continuous synthesis and breakdown of

triacylglycerols, with breakdown controlled largely via the activation of hormone-sensitive lipase

• Lack glycerol kinase; cannot recycle the glycerol of TAG

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Metabolic Profile of Adiposite tissue

Triacylglycerols are stored in tissue -> enormous reservoir of metabolic fuel

-> needs glucose to synthesis TAG;

-> glucose level determines if fatty acids are released into blood

Brown fat• A specialized type of adipose tissue, is

found in newborn and hibernating animals• Rich in mitochondria• Thermogenin, uncoupling protein-1,

permitting the H+ ions to reenter the mitochondria matrix without generating ATP

• Is specialized to oxidize fatty acids for heat production rather than ATP synthesis

Liver

• The major metabolic processing center in vertebrates, except for triacylglycerol

• Most of the incoming nutrients that pass through the intestines are routed via the portal vein to the liver for processing and distribution

• Liver activity centers around glucose-6-phosphate

• Glucose-6-phosphate– From dietary carbohydrate, degradation of

glycogen, or muscle lactate– Converted to glycogen– released as blood glucose, – used to generate NADPH and pentoses via the

pentose phosphate pathway, – catabolized to acetyl-CoA for fatty acid synthesis

or for energy production in oxidative phosphorylation

• Fatty acid turnover• Cholesterol synthesis• Detoxification organ

Figure 27.11Metabolic conversions of glucose-6-phosphate in the liver.

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Metabolic Profile of the Liver (Glucose)

Essential for providing fuel to brain, muscle, other organs

-> most compounds absorpt by diet

-> pass through liver -> regulates metabolites in blood

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Metabolic Activities of the Liver (Amino Acids)

α-Ketoacids (derived from amino acid degradation) -> liver’s own fuel

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Metabolic Activities of the Liver (Fatty Acids)

cannot use acetoacetate as fuel

-> almost no transferase to generate acetyl-CoA

Metabolic Profile of Kidney

Production of urine -> secretion of waste products

Blood plasma is filtered (60 X per day) -> water and glucose reabsorbed

-> during starvation -> important site of gluconeogenesis (1/2 of blood glucose)

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Food Intake, Starvation, and Obesity

Normal Starved-Fed Cycle:

1. Postabsorptive state -> after a meal

2. Early fasting state -> during the night

3. Refed state -> after breakfast

-> Major goal is to maintain blood-glucose level!

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Blood-Glucose

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Postabsorptive state

Glucose + Amino acids -> transport from intestine to blood

Dietary lipids transported -> lymphatic system -> blood

Glucose stimulates -> secretion of insulin

Insulin:

-> signals fed state

-> stimulates storage of fuels and synthesis of proteins

-> high level -> glucose enters muscle + adipose tissue (synthesis of TAG)

-> stimulates glycogen synthesis in muscle + liver

-> suppresses gluconeogenesis by the liver

-> accelerates glycolysis in liver -> increases synthesis of fatty acids

-> accelerates uptake of blood glucose into liver -> glucose 6-phosphate more rapidly formed than level of blood glucose rises -> built up of glycogen stores

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Insulin Secretion –Stimulated by Glucose Uptake

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Postabsorptive State -> after a Meal

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Early Fasting State

Blood-glucose level drops after several hours after the meal -> decrease in insulin secretion -> rise in glucagon secretion

Low blood-glucose level -> stimulates glucagon secretion of α-cells of the pancreas

Glucagon:

-> signals starved state

-> mobilizes glycogen stores (break down)

-> inhibits glycogen synthesis

-> main target organ is liver

-> inhibits fatty acid synthesis

-> stimulates gluconeogenesis in liver

-> large amount of glucose in liver released to blood stream -> maintain blood-glucose level

Muscle + Liver use fatty acids as fuel when blood-glucose level drops

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Early Fasting State -> During the Night

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Refed State

Fat is processed in same way as normal fed state

First -> Liver does not absorb glucose from blood (diet)

Liver still synthesizes glucose to refill liver’s glycogen stores

When liver has refilled glycogen stores + blood-glucose level still rises -> liver synthesizes fatty acids from excess glucose

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Prolonged Starvation

Well-fed 70 kg human -> fuel reserves about 161,000 kcal

-> energy needed for a 24 h period -> 1600 kcal - 6000 kcal

-> sufficient reserves for starvation up to 1 – 3 months

-> however glucose reserves are exhausted in 1 day

Even under starvation -> blood-glucose level must be above 40 mg/100 ml

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First priority -> provide sufficient glucose to brain and other tissues that are dependent on it

Second priority -> preserve protein -> shift from utilization of glucose to utilization of fatty acids + ketone bodies

-> mobilization of TAG in adipose tissues + gluconeogenesis by liver -> muscle shift from glucose to fatty acids as fuel

After 3 days of starvation -> liver forms large amounts of ketone bodies (shortage of oxaloacetate) -> released into blood -> brain and heart start to use ketone bodies as fuel

After several weeks of starvation -> ketone bodies major fuel of brain

After depletion of TAG stores -> proteins degradation accelerates -> death due to loss of heart, liver, and kidney function

Prolonged Starvation

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Mobilization at Starvation

Also at not treated diabetes

THE END

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