Le principali vie del metabolism

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					 Le principali vie del metabolismo energetico nei mammiferi

           proteine                               glicogeno                             triacilgliceroli
                                   sintesi del                Degradazione
                                   glicogeno                  del glicogeno



                                                 glucosio 6-P                            acidi grassi
         aminoacidi
                                     gluconeogenesi        glicolisi          sintesi degli         b-ossidazione
Degradazione          sintesi                                                 acidi grassi
degli                 degli                 ATP                  ATP
aminoacidi            aminoacidi

                                                   piruvato               ATP




                                                  acetilCoA
                                                                                  Corpi chetonici
                               ossalacetato         Ciclo              Fosforilazione
               urea                                 dell’acido         ossidativa
                                                    citrico
                                                                           ATP
                   Correlazioni metaboliche tra cervello, tessuto
                             adiposo, muscolo e fegato
                                                                Corpi chetonici
                                                                                     H2O + CO2
                                                                 glucosio



                                          Corpi chetonici       lattato       urea


                                             AcetilCoA         piruvato              aminoacidi


                                            Acidi grassi
                        Acidi grassi

                                          triacilgliceroli     glucosio               proteine
triacilgliceroli
                          glicerolo                glicerolo
                                                               glicogeno
                         glucosio

                                                                    lattato
                                                Alanina +
                                                glutamina
                                                                   piruvato           H2O + CO2
                           Acidi grassi
           CO2 + H2O                            aminoacidi
                                                                   glucosio

                       Corpi chetonici
                                                  proteine        glicogeno
    Vie di collegamento metabolico tra vari organi:
                     ciclo di Cori




     GLUCONEOGENESI
lattato             glucosio


   ATP + GTP   ADP + GDP + Pi
                                          glucosio         GLICOGENOLISI
                                                                 E
                                                             GLICOLISI
                                              glicogeno
                                                       ADP + Pi

                                                     ATP
                                lattato
                                SANGUE
   Vie di collegamento metabolico tra vari organi:
                  ciclo dell’alanina




      GLUCONEOGENESI
piruvato           glucosio

           NH3   urea

alanina                           glucosio              glicogeno

                                             piruvato
                                                        a-aminoacido
                              TRANSAMINAZIONE
                                                       a-chetoacido


                               SANGUE
                                             alanina
Relative changes in metabolic parameters during the
                onset of starvation




                                                       plasma insulin

                                                       plasma glucagon
   Relative change




                                                       liver glycogen

                                                       blood glucose

                                                       plasma free fatty acids

                                                       blood ketone bodies




                     0                         12-24
                         Hours of starvation
                  Glucose in numbers


 estimated consumption in humans: 8-10 g/h (~
50% by the brain)

 pool of circulating glucose: 5 g

 production in the overnight fasted state: ~ 65%
from liver glycogen breakdown and 35% from
splanchnic gluconeogenesis (18% from aminoacids,
14% from lactate, 2% from glycerol and 1% from
piruvate)

 in prolonged fasting (> 60 h) the contribution of
kidneys to glucose output raises to 20-25%
    Key sensors of cellular energy status and nutrient
        availability: the AMP/AMP-kinase system

 All living cells must continously maintain a high, non
equilibrium ratio of ATP to ADP

 Because of the adenylate kinase reaction (2ADP  ATP + Pi)
AMP raises whenever the ATP/ADP ratio falls

 High cellular ratio of AMP/ATP is a signal that the energy
status of the cell is compromized

 AMP-kinase is switched on by cellular stresses that interfere
with ATP production (hypoxia, glucose deprivation or ischemia)
or by stresses that increase ATP consumption (muscle
contraction)
Key sensors of cellular energy status and nutrient availability:
                         malonyl-CoA

  malonyl-CoA is a biochemical sensor that switches substrate
 oxidation from fatty acids to glucose (inhibition of CPT1 
 reduced lipid oxidation  lipid storage into triglycerides)

  Malonyl-CoA is produced by acetyl-CoA carboxylase, ACC (two
 isoforms). ACC1 is cytosolic, expressed in lipogenic cell types
 and involved in fatty acid synthesis. ACC2 is anchored in the
 mitochondrial membrane and is expressed in cell types where
 malonyl-CoA governs the entry of fatty acids into mitochondria
 (i.e. skeletal muscle)

  Both ACC1 and ACC2 are similarly regulated: by citrate, feed-
 forward allosteric activator; by AMP-K that phosphorylates and
 inactivates ACC

  Skeletal muscle also expresses malonyl-CoA decarboxylase
 (MCD) whose sole function is to decarboxylate malonyl-CoA to
 acetyl-Co-A
Key sensors of cellular energy status and nutrient availability:
                            glucose


  glucose is primarily used in the synthesis of glycogen and
 glycolysis but a small fraction (1-3%) enters the hexosamine
 biosynthesis pathway  UDP-N-actylglucosamine (protein
 glycosylation)
  nutrient-dependent post-transcriptional modification of
 enzymes, transporters, etc.
                        The aminoacid sensing system
Nearly half of the AAs present in protein
cannot be synthesized or stored in metazoans            Levels of amino acids in anterior
                                                        piriform cortex (APC) 20 min after
because the genes for their synthesis were                        introduction of
lost early in evolution; these are the essential
or dietary indispensable amino acids (IAAs).
                                                                         Diet deprived of
                                                        Normal diet
1. Maintenance of indispensable amino acid (IAA)                       indispensable amino
                                                                               acids
homeostasis is essential for protein synthesis and
survival, requiring dietary selection in omnivores
(animals adopt behavioral strategies some of which
are adaptive in the longer term and associated with
learning).
2. For appropriate dietary selection, sensing the
depletion of an IAA is a crucial first step.
3. The brain area housing the IAA sensor is the
anterior piriform cortex (APC).
4. The mechanism of IAA sensing in the APC is the
conserved general amino acid control pathway.
5. The four steps of the sensory mechanism are
decreased IAA, increased deacylated tRNA,
activation of GC nonderepressing kinase 2, and
phosphorylation of eukaryotic initiation factor 2α,
which binds to eIF2B and blocks initiation of
translation.
6. The APC is highly excitable and has oscillatory
activity coordinated with respiration.
7. Several signal transduction systems may be
involved in potentiating the output cells of the APC.
           Controllo ormonale del metabolismo: insulina

EFFETTI METABOLICI
• traslocazione dei GLUT4 (muscolo e tessuto adiposo)
• utilizzo del glucosio introdotto con la dieta (~50% glicolisi, ~ 30-
40% convertito in grassi, ~10% convertito in glicogeno)
• inibizione gluconeogenesi
• effetto ipoglicemizzante
• azione lipogenica e inibizione della lipolisi
• effetto anabolico (rallentamento della degradazione delle proteine)
• stimolazione della proliferazione (effetto mitogeno)

MECCANISMO D’AZIONE
legame e attivazione del recettore (tirosin chinasi)  attivazione di
una cascata di fosforilazione di proteine segnale 
1) traslocazione di proteine (es. GLUT4);
2) modulazione dell’attività enzimatica mediante defosforilazione
(es. glicogeno sintasi, fosforilasi chinasi, piruvato DH, piruvato
chinasi, PFK-2, fruttosio-2,6-bisfosfato fosfatasi, acetil-CoA
carbossilasi, HMG-CoA reduttasi, trigliceride lipasi);
3) regolazione della trascrizione genica (  glucochinasi, GAPDH,
piruvato chinasi, PEPCK, glucagone, etc.)
4) stabilità e traduzione mRNA
             Secrezione dell’insulina da parte delle cellule b del
                                  pancreas

            Captazione e metabolismo del glucosio
    (glicolisi accoppiata a ciclo degli acidi tricarbossilici)


                                                    UCP2

                                ATP/ADP
                                                                Mitochondrial proton leak




                                                                          ATP/ADP
                       secrezione dell'insulina
                         (glucosio-mediata)


   UCP2 is markedly upregulated in                              Reduced insulin secretion
         islets of ob/ob mice

Cell. 2001, 105(6):745-55 Uncoupling protein-2 negatively regulates insulin secretion and is a major
link between obesity, beta cell dysfunction, and type 2 diabetes
Insulin signaling: phosphorylation state of IRS1

          IR


                  Y-p                  Y-p
   p-Y
                         IRS-1         Y-p
                                             PI3K
   p-Y            Y-p


                                                     PKB
                   mTOR        PKC
   ERKs JNKs                         S6K



          p-S           S-p                                  Y-p
                                                    IRS-1     Y-p
    p-S         IRS-1         Y-p            p-S            Y-p


   REDUCED IRS1 FUNCTIONS                     ENHANCED IRS1 FUNCTIONS

   NEGATIVE FEEDBACK LOOP                      POSITIVE FEEDBACK LOOP
                           Impaired insulin signaling
           hyperinsulinemia
                                                      IRS-1 is phosphorylated by
                                                      the tyrosine kinase of the
                                Insulin receptor      insulin receptor in
JNK, PKC, IKKß, and TNFa                              response to insulin binding.


Hyperactivation of mTOR
                                      IRS-1     Protein/lipid kinase, PI 3-kinase,
by amino acids, Akt, or       Serine P          binds to the specific MYMX motifs
hyperinsulinemia results                        of IRS-1, containing
in serine phosphorylation           PI 3-kinase phosphorylated tyrosine residues.
of IRS-1 by p70S6 kinase,
with a subsequent
decrease in the strength of                    PI 3-kinase is then activated
the IRS-1/PI 3-kinase                   Akt
                                               and initiates a downstream
signaling. In addition,                        cascade of events leading to
serine phosphorylation of                      the phosphorylation and
IRS-1 can be promoted by             mTOR      activation of Akt, mTOR, and
JNK, PKC, IKKß, and TNFa.                      p70S6 kinase. Activation of Akt
                                               appears to be important for
                                  p70S6 kinase glucose transport, while
      Amino acids                              activation of mTOR and p70S6
                                               kinase participates in the
                                               process of protein synthesis.
               Impaired insulin signaling: PI3 kinase
                            Insulin receptor


                                 IRS-1           p85      GH, hPGH,
                                                          steroids,
                                                          overfeeding,
                                                p85       obesity, T2DM
                              p85     p110
                                                   p85

                                    Akt
 PI3 kinase is a heterodimer consisting of a catalytic (p110) and a
regulatory subunit. The most abundant isoform of the regulatory subunit is
p85
 Increased expression of p85 monomer competes with and displaces the
p85-p110 heterodimer from the IRS-1 binding sites. The resultant decrease
in association of p110 with IRS-1 diminishes PI 3-kinase activity and the
downstream effects of this kinase
 Steroids, growth hormone (GH), human placental growth hormone
(hPGH), short-term overfeeding, obesity, and type 2 diabetes (T2DM) have
been shown to increase p85 expression
               What is the metabolic syndrome?
The metabolic syndrome is characterized by a group of metabolic
risk factors in one person. They include:
   Central obesity (excessive fat tissue in and around the
  abdomen)
   Atherogenic dyslipidemia (blood fat disorders — mainly high
  triglycerides and low HDL cholesterol — that foster plaque
  buildups in artery walls)
   Raised blood pressure (130/85 mmHg or higher)
   Insulin resistance or glucose intolerance (the body can’t
  properly use insulin or blood sugar)
   Prothrombotic state
   Proinflammatory state

An apple may be good for you,
but an apple figure with excess
                                                  =
  weight in the middle, isn't.
             WHO HAS THE METABOLIC SYNDROME

 The metabolic syndrome has become increasingly common in
the United States. It’s estimated that about 20-25% of US
adults have it.


 The syndrome is closely associated with a generalized
metabolic disorder called insulin resistance, in which the body
can’t use insulin efficiently. This is why the metabolic
syndrome is also called the insulin resistance syndrome.


 Some people are genetically predisposed to insulin
resistance. Acquired factors, such as excess body fat and
physical inactivity, can elicit insulin resistance and the
metabolic syndrome in these people. Most people with insulin
resistance have central obesity. The biologic mechanisms at
the molecular level between insulin resistance and metabolic
risk factors aren’t fully understood and appear to be complex.
           Liporegulation, lipid partitioning, obesity

leptina   • Ormone peptidico (i recettori sono espressi prevalentemente a livello
          ipotalamico)
          • Prodotto del gene ob
          • Espressa nelle cellule del tesssuto adiposo
          • Regola negativamente la quantità di tessuto adiposo: aumenta quando
          si acquista peso e diminuisce quando si perde peso
          • Ha effetti sul metabolismo energetico (attiva AMP-K nel muscolo
          scheletrico quindi l’ossidazione degli acidi grassi)
          • Obesità spesso si correla a ridotta sensibilità all’azione della leptina

                  • Fattore prodotto e secreto da adipociti
Adiponectina
                  • ruolo nella sensibilità all’insulina (nel muscolo e nel
(ACRP30)          fegato)
                  • Attiva AMP-K in fegato e muscolo scheletrico dove
                  promuove ossidazione di acidi grassi e glucosio e inibisce la
                  gluconeogenesi
                  • i livelli circolanti diminuiscono in soggetti obesi e con
                  diabete di tipo II

          • Citochina proinfiammatoria prodotta da numerosi tipi
TNFa
          cellulari (anche adipociti)
          • induce insulino-resistenza
Liporegulation and lipid partitioning (IA)




   When normal healthy individuals are in
 caloric balance, their liporegulatory system
       is at rest (leptin levels are low)
        Liporegulation and lipid partitioning (IB)




  When normal healthy individuals chronically consume more
    calories than are needed to meet the caloric expenditure,
adipocytes will expand and leptin levels will rise in proportion to
 the degree of lipid overload. By promoting fatty acid oxidation
and deterring lipogenesis the hyperleptinemia maintains the lean
          tissue content of lipids at a near-normal level.
Lipid partitioning in diet-induced obesity

                Resistance to leptin
                in its target tissues




                                          Lipid storage in lean
                                            tissues leads to
                                        dysfunction (lipotoxicity)


   In visceral obesity the circulating level of
 leptin although higher than normal may not
      be high enough to provide effective
                  antisteatosis
        Generalized obesity




Hyperleptinemia, better ability to limit
     ectopic lipid accumulation
                      Fructose and insulin resistance
 High-fructose diets have been shown to induce insulin resistance, weight gain,
 hyperlipidemia, and hypertension in several animal models.
 In human studies, fructose consumption was associated with the development of
 hepatic and adipose tissue insulin resistance and dyslipidemia due to its ability to
 induce hepatic de novo lipogenesis

                        fructose
     FRUCTOKINASE
      Km < 0.5 mM
                      fructose-1-P

   Dihydroxy                    ALDOLASE B
   acetone-P
                    glyceraldehyde              TRIOKINASE

 Glycerol-3P
                       glycerol           glyceraldheyde-3P             dihydroxyacetone-P


                                              piruvate
                                                                lactate
                                             acetyl-CoA
              Fatty acids

Fructose and the metabolic syndrome: pathophysiology and molecular mechanisms. Nutr Rev. 2007 65:S13-23
         SREBPs: caratteristiche e regolazione

SREBP-1a: codificata dallo stesso gene che codifica per SREBP-1c.
Il gene presenta due siti di inizio della trascrizione e due esoni 1.
L’esone 1a codifica per un segmento più lungo con una maggiore
capacità di transattivazione.
SREBP-1c: effetto sulla trascrizione più ristretto rispetto a SREBP-
1a.
SREBP-2: codificata da un gene distinto da quello che codifica per
SREBP-1a/c.


             REGOLAZIONE DELL’ATTIVITA’ DI SREBP

• a livello della trascrizione
(insulina, LXR inducono SREBP-1c)

• a livello post-traduzionale (proteolisi)
                           Genes regulated by SREBPs

                                                                  In vivo, SREBP-1c preferentially
In vivo, SREBP-2
                                                                  activates genes of fatty acid and
preferentially activates genes
                                                                  triglyceride metabolism
of cholesterol metabolism




        DHCR 7-dehydrocholesterol reductase         G6PD, glucose-6-phosphate dehydrogenase
        FPP farnesyl diphosphate                    PGDH 6-phosphogluconate dehydrogenase
        GPP geranylgeranyl pyrophosphate synthase   GPAT glycerol-3-phosphate acyltransferase.
        CYP51 lanosterol 14α-demethylase.
              PPARs: caratteristiche e funzioni


• Peroxisome proliferator-activated receptors (PPARs) are nuclear
hormone receptors that mediate the effects of fatty acids and their
derivatives at the transcriptional level.
• These receptors stimulate transcription after activation by their
cognate ligand and binding to the promoter of target genes.
• Several PPAR subtypes have been described and named PPARa,
PPARb/d, PPARg,. The different forms are expressed in tissue-specific
patterns and exhibit distinct functions:
PPARa is abundantly found in liver, kidney, heart, and muscle (fatty
acid catabolism and modulation of the inflammatory response);
PPAR is localized in fat, large intestine, and macrophages (adipocytic
differentiation, monocytic differentiation and cell cycle withdrawal);
PPARb/ are widely expressed (embryo implantation, cell proliferation
and apoptosis)
PPARa: effetti metabolici

        very long chain fatty acids,
        branched chain fatty acids,
               pristanic acid


                PPARa ligands



                Transcription
                 activation            oxidation

  Lipid
 binding
 protein




Microsomal                       peroxisomal b-
w-oxidation                        oxidation


                Mitochondrial
                 b-oxidation

 Dicarboxylic                          oxidation
    acids
                //
                         PPAR: effetti metabolici
                                                                     FFAs
                                                           insulin resistance: TNFa
 insulin sensitivity:                                        insulin sensitivity:
     ACRP30                                                        ACRP30


                     glucose uptake           GLUT4
            lipid uptake and storage          CD36, FATP, aP2, ACS, etc.
                 energy expenditure           glycerol kinase, UCP2, UCP3
            regulate secreted factors           ACRP30,  TNFa, leptin
                                         PPAR
                                        agonists


    lipid uptake and storage        CD36, aP2
         energy expenditure         UCP2



                          gluconeogenesis
                              PEPCK
                                                        glucose oxidation:
                                                              PDK4
          LXRs: caratteristiche e funzioni
Two genes encode highly conserved isoforms.
LXRa: expressed in tissue specific manner
LXRb: ubiquitously expressed
Upregulated by PPARg.
Target genes: CYP7A1 (bile acid synthesis), ABC
transporters (cholesterol efflux), ApoE (cholesterol
acceptor), CETP (lipoprotein remodeling), LPL, SREBP1-c
(fatty acid metabolism), LXRa.




                       Role of LXRs
                 Cholesterol homeostasis
                   Glucose metabolism
Mechanisms underlying LXR-mediated regulation of gene
                    transcription




                                                       Oxysterols
                                                       glucose
               Oxysterols
               glucose            RXR LXR          +
                                  LXRE             Transcription factor
 RXR LXR   +                            TF                 SREBP-1c
  LXRE     Target gene           TF
                                         TF
               ABCA1
               apoE
                                        TF                +
                                      Responsive         Target gene
                                       element
                                                       Fatty acid synthase
          LXRs: effetto sull’omeostasi del colesterolo
                                                                                      ABSORPTION
                                            DIET
                                                                    INTESTINAL LUMEN
                            BLOOD

                     ABCs    HDL                     cholesterol
       cholesterol
                     apoE
                                                                   Bile acids
                                                                                   ABCs
  macrophage

                                                     ABCs
EFFLUX AND TRANSPORT                                                            cholesterol

                                       cholesterol
                                CYP7A1


                                   -   Bile acids

                                                                                      EXCRETION


                                        CATABOLISM
       ROLE OF FATTY ACID AND OXYSTEROL SENSING
  RECEPTORS IN THE CONTROL OF METABOLIC PATHWAYS (I)

                      GLUCOSE METABOLISM

• LXRa acts as insulin-sensitizer in liver and adipose tissue where
it represses gluconeogenesis and promotes glucose uptake and
storage
induction of GK and repression of gluconeogenetic genes in liver

• PPARa stimulates hepatic gluconeogenesis to meet the
metabolic needs of the body during fasting by inducing
conversion of glycerol that is produced in adipose tissue through
lypolisis, into glucose in the liver.
Up-regulation of hepatic glycerol 3P dehydrogenase, glycerol kinase and
glycerol transporters

• PPAR mediates insulin action in insulin-sensitive tissues
promoting glucose utilization in skeletal muscle, repressing
gluconeogenesis in the liver, and contributing to inter-organ
cross-talk
   ROLE OF FATTY ACID AND OXYSTEROL SENSING RECEPTORS
        IN THE CONTROL OF METABOLIC PATHWAYS (II)

                        FATTY ACID METABOLISM
• PPARa is a master regulator of fatty acid utilization in the liver
during the fasted state
Induction of genes involved in fatty acids oxidation. PPARa inactivation leads to
hypoketonemia, hypothermia, elevated free fatty acids, hypoglycemia

• the regulatory circuit involving LXRa and SREBP-1c is
responsible for the lipogenic response of the liver and adipose
tissue to insulin
Induction of FAS and other genes involved in fatty acid synthesis. Insulin
regulates Srebp-1c transcription through an LXRE

• PPAR and LXRa are required for adipocyte differentiation and
lipogenic activity of adipose tissue

• PPARb/ is mainly involved in fatty acid utilization and energy
dissipation in adipose tissue and skeletal muscle (control of
adiposity and adaptation of fibers in skeletal muscle to
endurance exercise)
  ROLE OF FATTY ACID AND OXYSTEROL SENSING RECEPTORS
      IN THE CONTROL OF METABOLIC PATHWAYS (III)

                     CHOLESTEROL METABOLISM



• LXRs participate to the physiological repression of cholesterol
synthesis under normal conditions
Genetic inactivation of LXRs leads to derepressed cholesterol synthesis

• LXRs positively regulate the transport of cholesterol from
extrahepatic tissues to the liver acting on different target genes

• LXRs are sensors of dietary cholesterol and facilitate
elimination of excess cholesterol through bile acids in rodents

• activation of PPARa in the liver may lead to decreased bile acid
synthesis and secretion into bile

				
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