STARVE-FEED CYCLE 1) WELL-FED STATE (food intake insulinemia) - the diet supplies the energy requirements GLUCOSE liver

iver 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) 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 used by the muscle as an energy fuel stored in the adipose tissue (= energy storage) synthesis of VLDL in the liver

AMINO ACIDS

LIPIDS

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 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) used in gluconeogenesis (glucogenic amino acids) amino nitrogen detoxicated by urea synthesis glutamine metabolized in enterocytes 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

AMINO ACIDS

LIPIDS

4) EARLY REFED STATE ( insulinemia) - normal glucose metabolism is slowly reestablished 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) synthesis of proteins (liver + other tissues) transformation to glycogen in the liver used by the muscle as an energy substrate stored in the adipose tissue (= energy storage)

AMINO ACIDS

LIPIDS

OTHER IMPORTANT INTERORGAN METABOLIC INTERACTIONS LYMPHOCYTES, MACROPHAGES rapidly dividing cells: need substrates for purine and pyrimidine synthesis Gln nucleotide synthesis or partial oxidation to Asp blood

ENTEROCYTES 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 LIVER glutathione synthesis glutathione blood kidney and the other tissues glutathione bile enterocytes synthesis of carnitin blood especially to the muscle and the heart (-oxidation) 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 (-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 (= -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 signal substance (e.g. hormones) signal transduction into a cell change in an enzyme activity (= final goal of the regulation)

B) Regulation on the cell level compartmentalization of metabolic pathways change of activity of an existing enzyme change of concentration of an enzyme

Compartmentalization of metabolic pathways various distribution of enzymes, substrates and products velocity of transport processes among compartments

Change of activity of an existing enzyme 1) in relation to enzyme kinetics 2) low concentration of regulatory enzymes low concentration of substrates (< Km) substrate specifity - different Km product consumption pH changes

modulators of enzyme activity feed back inhibition cross regulation feed forward activation isosteric or allosteric modulation competitive inhibition T-form / R-form of the enzyme

3)

covalent modification of an enzyme reversible phosphorylation and dephosphorylation (interconversion of enzymes by protein kinase or protein phosphatase respectively)

Change of concentration of an enzyme induction / repression change of gene expression Vladimra Kvasnicov