Download STARVE-FEED CYCLE 1) WELL-FED STATE (food intake

STARVE-FEED CYCLE
1) WELL-FED STATE (food intake ⇒ ↑ insulinemia) - the diet supplies the energy requirements
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GLUCOSE
→ liver and muscle glycogen synthesis (= energy storage)
→ synthesis of fat in the adipose tissue (= energy storage)
→ synthesis of fat in the liver → VLDL
→ used by all tissues as an energy fuel
→ Cori cycle is interrupted (lactate is converted to fat)
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AMINO ACIDS
→ Asp, Asn, Glu, Gln are metabolized by enterocytes to Ala, lactate,
citrulline and Pro, which are released into portal blood
→ synthesis of proteins (liver + other tissues)
→ oxidation to CO2 and H2O + synthesis of urea
→ transformation to fat in the liver → VLDL
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LIPIDS
→ used by the muscle as an energy fuel
→ stored in the adipose tissue (= energy storage)
→ synthesis of VLDL in the liver
2) EARLY FASTING STATE (↓ insulinemia, ↑ glucagonemia) - hepatic glycogenolysis is an important
source of blood glucose
• GLUCOSE
→ main energy fuel
→ released from liver glycogen
→ resynthesized from lactate (Cori cycle) and alanine (released from the
muscle = glucose / alanine cycle)
3) FASTING STATE (↓ insulinemia, ↑ glucagonemia) - gluconeogenesis from amino acids and glycerol
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GLUCOSE
→ used as an energy fuel by glucose-dependent tissues (brain, ery)
→ resynthetized from lactate (Cori cycle)
→ gluconeogenesis from glycerol released from adipose tissue
→ gluconeogenesis from proteins (main amino acids: alanine, glutamine)
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AMINO ACIDS
→ used in gluconeogenesis (glucogenic amino acids)
→ amino nitrogen detoxicated by urea synthesis
→ glutamine metabolized in enterocytes
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LIPIDS
→ main energy fuel
→ liver: fatty acids are transformed to ketone bodies (= the alternative
energy fuel for extrahepatic tissues containing mitochondria)
→ glycerol is used as a substrate of the gluconeogenesis
→ brain starts metabolized keton bodies in addition to glucose
4) EARLY REFED STATE (↑ insulinemia) - normal glucose metabolism is slowly reestablished
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GLUCOSE
→ used as an energy fuel
→ liver remains in the gluconeogenesis for a few hours → glycogenesis
→ indirect synthesis of glycogen in the liver (from lactate)
→ synthesis of glycogen in the muscle (= energy storage)
→ synthesis of fat in the adipose tissue (= energy storage)
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AMINO ACIDS
→ synthesis of proteins (liver + other tissues)
→ transformation to glycogen in the liver
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LIPIDS
→ used by the muscle as an energy substrate
→ stored in the adipose tissue (= energy storage)
OTHER IMPORTANT INTERORGAN METABOLIC INTERACTIONS
LYMPHOCYTES, MACROPHAGES
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rapidly dividing cells: need substrates for purine and pyrimidine synthesis
Gln → nucleotide synthesis or partial oxidation to Asp → blood
ENTEROCYTES
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rapidly dividing cells: need substrates for purine and pyrimidine synthesis
Gln → nucleotide synthesis or partial oxidation to Ala → blood (Ala is then metabolized in the liver)
Gln → citrulline (it is then metabolized in the kidney to Arg) ⇒ regulation of urea cycle is related to
Gln metabolism which is related to amino acid degradation in the body
KIDNEY
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citrulline from blood → Arg
Arg → creatine → blood → muscle → creatine phosphate
Arg → blood → all cells: Arg → protein synthesis / many cells: Arg → NO / liver: Arg → urea cycle
synthesis of carnitine → blood → especially to the muscle and the heart (β-oxidation)
LIVER
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glutathione synthesis
glutathione → blood → kidney and the other tissues
glutathione → bile → enterocytes
synthesis of carnitin → blood → especially to the muscle and the heart (β-oxidation)
REGULATION OF METABOLISM
4 principal mechanisms:
1) substrate supply
2) allosteric effectors
3) covalent modification of enzymes
4) induction - repression of enzymes
1) substrate supply
• major determinant of the rate at which every metabolic processes of the body operates:
• blood fatty acids concentration → ketogenesis in the liver
• excessive amounts of substrates → synthesis of excess fat
• gluconeogenic substrates → rate of gluconeogenesis
• ↑ Gln → ↑ citrulline → ↑ urea synthesis
2) allosteric effectors (negative or positive)
• ↑ glucose: inhibits glycogen phosphorylase, activates glycogen synthase (= mtb of glycogen)
• ↑ fructose-2,6-bisphosphate (↑ if insulin is ↑): inhibits fru-1,6-bisphosphatase (= gluconeogenesis),
activates 6-PFK-1 (= glycolysis)
• ↑ citrate: inhibits 6-PFK-1 (= glycolysis), activates acetyl-CoA carboxylase (= fatty acid synthesis)
• ↑ acetyl-CoA: inhibits pyruvate dehydrogenase, activates pyruvate carboxylase (= activation of
gluconeogenesis)
• ↑ malonyl-CoA inhibits carnitine palmitoyl transferase I (= β-oxidation)
3) covalent modification of enzymes
• phosphorylation (protein kinases) / dephosphorylation (protein phosphatases)
• some phosphorylated enzymes are active (glycogen phosphorylase) other inactive (glycogen
synthase)
4) change in the cellular level of a key enzyme (longer time adaptive mechanism)
• change in the rate of synthesis or degradation of the enzyme - hormonal and nutritional factors
• well-fed state: the liver improves its capacity to synthesize fat
• fasting: ↓ in quantity of lipogenetic enzymes; enzymes of gluconeogenesis are induced (↑ synthesis)
A) Regulation on the organism level
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signal substance (e.g. hormones)
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signal transduction into a cell
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change in an enzyme activity (= final goal of the regulation)
B) Regulation on the cell level
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compartmentalization of metabolic pathways
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change of activity of an existing enzyme
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change of concentration of an enzyme
Compartmentalization of metabolic pathways
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various distribution of enzymes, substrates and products
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velocity of transport processes among compartments
Change of activity of an existing enzyme
1)
in relation to enzyme kinetics
2)
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low concentration of regulatory enzymes
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low concentration of substrates (< Km)
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substrate specifity - different Km
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product consumption
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pH changes
modulators of enzyme activity
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feed back inhibition
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cross regulation
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feed forward activation
→ isosteric or allosteric modulation
↓
competitive inhibition
3)
↓
T-form / R-form of the enzyme
covalent modification of an enzyme
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reversible phosphorylation and dephosphorylation (interconversion of enzymes by protein
kinase or protein phosphatase respectively)
Change of concentration of an enzyme
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induction / repression → change of gene expression
Vladimíra Kvasnicová