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  • Intermediary metabolism

    Eva Samcová

  • Metabolic roles of tissues • Four major tissues play a dominant role in fuel

    metabolism : liver, adipose, muscle, and brain.

    • These tissues do not function in isolation.

    • Communication between tissues is mediated by the nervous systém, by the availability of circulating substrates, and by variation in the levels of plasma hormones.

    • The integration of energy metabolism is controlled by the actions of two peptide hormones, insulin, and glucagon (response to changing substrate levels) with catecholamines epinephrine and norepinephrine (response to neural signals).

  • Liver

    Liver lies immediately under the diaphragm. It is supplied

    with blood from below through two major vessels: the

    hepatic artery (20% of blood) and the hepatic portal vein

    which brings the substrates (soluble in water) absorbed

    from the intestinal tract including stomach into the blood

    and then directly to liver.

    Pancreatic vein (insulin, glucagon)

    Liver consumes 20 – 30% of total oxygen consumption

  • Functions of the liver The uptake of nutrients delivered from the

    digestive tract via portal vein

    The synthesis, storage, interconversion and

    degradation of metabolite

    The regulated supply of energy-rich

    intermediates

    The detoxification of harmful compounds by

    biotransformation

    The excretion of substances with the bile;

    synthesis and degradation of many blood plasma

    constituents

  • Carbohydrate metabolism in the liver- fed

    conditions

     Concentration in portal vein after a meal up to 10 mmol/l – GLUT-2 –

    type glucose transporter not responsive to insulin, relatively high Km

    (rate and direction of movement of glucose through hepatocyte

    membrane are determined by concentration inside and outside the cell)

     Glucokinase (Km= 12 mmol/l) x hexokinase 0.1 mmol/L

     Any increase in glucose concentration against blood conc. leads to

    proportional increase in the rate of phosphorylation by glucokinase

    .Likewise any decrease in glucose conc. leads to proportional decrease

    in the rate of phosphorylation.

     Thus liver uses glucose at significant rate only when blood glucose level

    is greatly elevated.

     The overall result is that when glucose conc. outside the hepatocyte

    rises, glucose will be rapidly taken into cells and phosphorylated.

  • Carbohydrate metabolism in the liver-

    fed conditions

     The presence of high-Km glucose transporter and

    high-Km glucokinase do not enable the hepatocyte

    to take up unlimited quantities of glucose as G-6-P

     There are specific mechanisms for stimulating the

    disposal of Glu-6-P

     Glycogen synthesis (activation of glycogen

    synthase by insulin and glucose)

     Glycolysis metabolizes glucose to pyruvate 

    TCA, some released after conversion to lactate.

    But minor energy source for liver.

  • Metabolic Fate of G6P

  • Carbohydrate metabolism –

    overnight fasted conditions

     Glycogen breakdown (glycogenolysis), controlled by

    reciprocal activation of glycogen phosphorylase by

    glucagon, adrenalin, noradrenalin, catecholamines.

     Glu-1-P produced by glycogenolysis is in equilibrium

    with Glu-6-P (enzyme phosphoglucomutase).

     Formation of glucose from Glu-6-P is produced by

    enzyme Glu-6-phosphatase (membrane ER)

    12/2/12

  • Carbohydrate metabolism in the liver

     Synthesis of glucose – gluconeogenesis

     Substrates : lactate, alanine, glycerol

     Hepatic gluconeogenesis can be also stimulated by

    increase in the supply of substrate from other tissue

    (after physical exercise-lactate, starvation-glycerol)

    and by hormones (glucagon)

     Glucose paradox (gluconeogenesis after meal)

     The pentose phosphate pathway – alternative fate for

    Glu-6-P, conversion to five-carbons sugars (ribose-5-

    P for synthesis of nucleic acids)

     Formation of NADPH for reductive synthesis

  • Fat metabolism in the liver

     The metabolism of lipids in the liver is closely

    linked to metabolism of carbohydrates and

    amino acids.

     The pathwayof FA oxidation diverges from that

    of glycerolipid synthesis when acyl-CoA enters

    the mitochondrion for oxidation.

     Carnitine-palmitoyl transferase-1 (CPT-1).

    Activity of this enzyme is strictly regulated by

    means of compound malonyl-CoA (potent

    inhibitor). This role of malonyl-CoA provides a

    vital link between carbohydrate and fat

    metabolism.

  • Fat metabolism in the liver

     The liver converts glucose (Glc) via Acetyl-CoA into

    fatty acids (FA) - cytosol. FA and chylomicrons are

    used as a sources – neutral fats and phospholipides. In

    humans FA synthesis from other molecules (Glc) is

    usually small in comparison with dietary fatty acid

    intake.

     VLDL are formed in smooth ER of hepatocytes.

     High concentration of acetyl-CoA (postabsorptive

    state, starvation) as a result of β-oxidation of FA in

    mitochondrion  great amount of ketone bodies :

    acetoacetate, 3-hydroxybutyrate and acetone.

    12/2/12

  • Fat metabolism in the liver

     Cholesterol has two sources, the diet and de

    novo synthesis (in liver significant amount).

     Some cholesterol is required for synthesis of bile

    acids, some for cell membranes, some is stored

    in the form of lipids droplets in esterified form.

     The rest in free and esterified form in VLDL (to

    supply another tissues)

     The liver also degrades lipoprotein complexes

    (with cholesterol and cholesterol esters) taking

    up from the blood.

  • Amino acid metabolism in the liver

     Our bodies do not continuously accumulate or

    lose protein in a net sense. The rate of AA

    oxidation in the body must therefore balance the

    rate of entry of dietary protein (70-100g per day)

     Catabolism of AA occurs predominantly in the

    liver with exceptions (branched chain amino

    acids in muscles)

     AA oxidation provides ½ of the liver´s energy

    requirements

     It is also the only organ capable of eliminating

    the nitrogen from amino acids by urea cycle

  • Starve-Feed Cycle

    • The starve-feed cycle allows a variable fuel and nitrogen consumption to meet a variable metabolic and anabolic demand. Feed refers to intake of meals (variable fuel) after which we store the fuel in the form of glycogen and fat, to meet our metabolic demand while we fast. ATP is energy-transferring agent in this cycle.

  • Well-Fed State – Amino acids  Dietary proteins are hydrolyzed in the intestine (some

    of them are used like energy source here : Asp, Asn, Glu, Gln→Ala, Lac, citrul, Pro into the portal blood)

     Liver lets most of AA coming from intestine pass through, for synthesis of proteins in peripheral tissue , thanks to high Km .High Km allows to AA to be in excess without catabolism.

     Utilization of AA for proteosynthesis (much lower

    Km for tRNA-charging enzymes)

     Excess of AA can be oxidized to CO2 , water, urea, or metabolites can be used as substrates for lipogenesis

  • Well-Fed State - glucose

     Glucose → glycogen (glycogenesis), pyruvate, lactate

    (glycolysis), for pentose phosphate pathway

    (NADPH)

     Much of glucose from intestine passes through liver

    to reach other organs (brain, testis, RBC, renal

    medulla, AT)

     Number of tissues produce lactate and pyruvate from

    circulating glucose, which are taken up by liver , and

    fat is formed lipogenesis)

     In well-fed state liver does not engage in

    gluconeogenesis

     Cori cycle is interrupted

  • Well-βFed State – fat

     Glucose, lactate, pyruvate and AA support hepatic lipogenesis.

     Fat formed from these substrates is released in the form of VLDL

     Chylomicrons, VLDLs circulate in the blood until they meet lipoprotein lipase (near AT), hydrolysis of TAG (FA taken up adipocytes, reesterified with glycerol-3-phosphate to form TAG)

     During well-fed state insulin from cells of the pancreas is in high concentration. These cells are very responsive to the influx of glucose and AA in the fed state.

     Rate of insulin/glucagon

  • Well-Fed State

  • Early fasting state

     Hepatic glycogenolysis

     Lipogenesis is curtailed

     Lactate, pyruvate and AA are diverted into formation

    glucose completing Cori cycle (conversion glucose to

    lactate, pyruvate in peripheral tissue, they are

    substrates for gluconeogenesis in liver)

     Alanine cycle, in which carbon and nitrogen retu

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