Aminoacidi

Modello
temporaneo
(molto)
semplificato dei circuiti del SNC
implicati nell’anoressia e nella
cachessia del portatore di tumore
Cortisolo
+
Neuropeptidi orexigenici
-
NPY
Leptina
e insulina
Recettore per la melanocortina,
+
+
MCR
Neuropeptidi anorexigenici
CRH
Lipolisi
norepinefrina,
dopamina,
serotonina
Controllo
dell’appetito
Termogenesi  e
metabolismo
basale 
Modello
temporaneo
(molto)
semplificato dei circuiti del SNC
implicati nell’anoressia e nella
cachessia del portatore di tumore
Tumore
IL-1, TNFa,
IFNg
Neuropeptidi orexigenici
+
-
NPY
-
Recettore per la melanocortina,
Leptina
e insulina
+
MCR
+
Neuropeptidi anorexigenici
CRH
+
+
IL-1, TNFa,
IFNg
Tumore
norepinefrina,
dopamina,
serotonina
Tumore
Lipolisi
Anoressia
Termogenesi  e
metabolismo
basale 
Regulation of NPY production in the hypothalamic arcuate nucleus.
Glucocorticoids stimulate hypothalamic production of neuropeptide Y (NPY), leading
to increased food intake and reduced energy expenditure. Leptin, which is produced
by adipose tissue, blocks NPY production, as does insulin, which is produced by the
pancreas, and increased NPY decreases leptin and insulin production.
Digiuno post-prandiale (5-6 h)
Aminoacidi
GLUCOSIO
ACIDI GRASSI
_
catecolamine
insulina
Digiuno prolungato (1-7 giorni)
Proteine
GLUCOSIO
Aminoacidi
+
CORPI
CHETONICI
glucagone
ACIDI GRASSI
N ureico nelle
urine 
(da 12 a 2 g/24 h)
Digiuno protratto
GLUCOSIO
Tessuti
Aminoacidi
+
glucagone
CORPI
CHETONICI
Controllo dell’ossidazione degli acidi grassi
*
*insulina
glucagone
Chetogenesi
Keton bodies
in absence of
oxalacetate
CARATTERISTICHE ENDOCRINO-METABOLICHE DEL SOGGETTO DIGIUNANTE E DEL PORTATORE DI TUMORE
Nel soggetto digiunante




Aumento della lipolisi
Blocco della sintesi de novo degli acidi grassi
Inibizione della lipogenesi
Inibizione della lipasi lipoproteica (iperlipemia)
 Aumento della proteolisi muscolare
 Aumento dell’azoto ureico nelle urine
 Riduzione della sintesi proteica nei muscoli
scheletrici
 Aumento della sintesi epatica delle proteine della
fase acuta
(digiuno prolungato)
 Riduzione del metabolismo basale
 Insulinemia ridotta
 Cortisolo nel siero non modificato
 Aumento della gluconeogenesi dagli aminoacidi, dal
glicerolo, dall’acido lattico (prodotto dal tumore e
dai tessuti dell’ospite)
 Resistenza all’insulina
 Iperinsulinemia
 Intolleranza al glucosio
 Aumento del metabolismo basale
 Insulinemia fortemente aumentata
 Cortisolo nel siero aumentato
Tumore
(TNFa)
ACIDI GRASSI
TRIGLICERIDI
-
(TNFa)
Tumore
Effetto del tumore sulla sintesi e sull’utilizzazione
degli acidi grassi dopo il pasto
N ureico nelle
urine   
Sintesi
proteica 
PROTEINE
Corpi chetonici
tessuti, tumore
lattato
TNFa
PIF
Aminoacidi
Aminoacidi
Corpi chetonici
TNF
Sintesi delle proteine
della fase acuta
Caratteristiche metaboliche
del portatore di tumore
Breve storia della scoperta del ruolo delle citochine infiammatorie
nella cachessia neoplastica
Cerami e coll. negli anni ‘70 osservano in conigli affetti da tripanosomiasi una
notevole riduzione della massa corporea proteica e lipidica associata a una
marcata iperlipidemia come risultato di una ridotta attività lipoproteinlipasica;
Kawakami e Cerami nel 1981 dimostrano che il trattamento con endotossine
batteriche induce nel topo la comparsa di un fattore serico capace di sopprimere
l’attività lipoprotein-lipasica;
Beutler e Cerami nel 1985 dimostrano che il fattore inibitorio dell’attività lipoproteinlipasica corrisponde a una molecola polipeptidica, di origine macrofagica, a
struttura ben definita che viene denominata cachettina;
Beutler e Cerami nel 1986 dimostrano che la sequenza aminoacidica della
cachettina è omologa a quella del fattore di necrosi tumorale (TNF);
Successivamente l’analisi genetica ha confermato che la cachettina e il TNF sono
molecole identiche.
Catabolic mediators in cancer.
Both tumor-derived and humoural (cytokines) factors
are involved in mediating anorexia and metabolic
changes, characteristic of the cachectic state.
ATP
GLUCAGONE
+
ESOCHINASI
GLUCOSIO 6-FOSFATASI
GLUCOCHINASI
INSULINA +
GLUCAGONE_--_
ADP
ATP
GLUCAGONE
+
FRUTTOSIO
1,6-DIFOSFATASI
FOSFOFRUTTOCHINASI
INSULINA +
GLUCAGONE_--_
ADP
ADP
ADP
ATP
GLICEROCHINASI
ATP
GLICEROLO
ADP
INSULINA +
GLUCAGONE_--_
PIRUVATO CHINASI
GDP
GLUCAGONE
+
ATP
LATTATO
FOSFOENOLPIRUVATO
CARBOSSICHINASI
GTP
ATP
PIRUVATO CARBOSSILASI
ADP
PROPIONATO
MF
Cori cycle with sources of gluconeogenic substrates. Tumours produce factors such as
lipid-mobilizing factor (LMF), which induces breakdown of adipose tissue into fatty acids, and
proteolysis-inducing factor (PIF), which induces protein degradation (amino acids) in skeletal
muscle. Tumour necrosis factor (TNF)-a also contributes to these processes. These are
important gluconeogenic substrates that can be used in acute-phase protein (APP) synthesis
by the liver. Tumours convert glucose to lactate, which is transferred to the liver, where it is
converted back into glucose. This cycle uses a large amount of energy, and might contribute
to cachexia.
Synthesis and degradation of proteins in skeletal muscle. Protein levels in muscle are determined by the amount of
dietary intake of protein and levels of protein synthesis. Decreases in plasma insulin concentrations or insulin sensitivity of
skeletal muscle can activate three main proteolytic pathways that underlie protein catabolism in skeletal muscle. These
are the lysosomal system, which proteolyses extracellular proteins and cell-surface receptors; the cytosolic calciumactivated system, which involves calpains I and II and is involved in tissue injury, necrosis and autolysis, and the ATPubiquitin-dependent proteolytic pathway. This proteolysis leads to hepatic production of acute-phase protein (APP), which
can limit the availability of certain amino acids for protein synthesis in skeletal muscle. Protein deamination also leads to
nitrogen excretion, producing a negative nitrogen balance, and glucose production, which increases muscle activity.
Ubiquitin-proteasome pathway Ubiquitin (Ub)
The Ubiquitin–Proteasome Pathway of Proteolysis.
Indicazioni sulla partecipazione del sistema ubiquitinico nella
proteolisi dei muscoli scheletrici nella cachessia neoplastica
Aumento dell’mRNA dell’ubiquitina del muscolo retto-addominale di portatore di
cancro gastrico
Aumento delle subunità alfa e beta del proteosoma nei muscoli del portatore di
tumore
Aumentata espressione dell’enzima E2 che coniuga l’ubiquitina alle proteine
Aumentata espressione dell’enzima E3 legante la proteina
Muscle breakdown. Signaling pathways that regulate protein homeostasis in skeletal muscle. Cytokines such as TNF-a
together with IFN-g activate the transcription factor NF-kB. This leads to decreased expression of MyoD, a transcription
factor that may be important for replenishing wasted muscle. Activated NF-kB also acts as a repressor of proteasome
subunit expression and hence suppresses protein degradation, an activity that is antagonized by glucocorticoids. (The
proteasome is a multisubunit complex involved in the breakdown of ubiquitinated proteins.) Tumor factors such as PIF
increase production of proteasome subunits through the intermediary 15-HETE. It is not known whether this is a direct or
indirect effect (dashed arrows). Eicosapentaenoic acid (EPA) inhibits 15-HETE production in response to PIF and
prevents muscle wasting in cancer patients.
Interactions between pro-inflammatory cytokines and PIF
The Importance of Myosin in Cachexia. Soluble factors released from tumors or immune effector cells and implicated in
cachexia can lead to a specific decrease in the levels of the myosin heavy chain, a muscle contractile protein. The data
provide support for the existence of two pathways. In Panel A, the combination of tumor necrosis factor a (TNF-a) and
interferon- g (IFN-g) results in the suppression of the nuclear transcription factor MyoD and, hence, a decrease in the
transcription of the myosin heavy chain; a deficit in the cellular pool of myosin heavy chain results in cachexia.
Cytokines such as interleukin-6 increase the production of ubiquitin and E3 ubiquitin ligase proteins. In Panel B,
stimulation of the ubiquitin ligase–dependent proteasome pathway leads to increased and preferential ubiquination of
the myosin heavy chain, causing the dissociation of myosin from the contractile apparatus and its subsequent
degradation into peptides by the proteasomes. The loss of functional contractile units, probably combined with the
selective loss of other specific proteins, leads to muscle atrophy and wasting.
Proton transport by UCP1 across the inner mitochondrial membrane Normally, proton transport across the inner mitochondrial
membrane is coupled to phosphorylation of ADP to generate ATP. An increase in membrane proton permeability that is not coupled
to an energy-consuming system constitutes a proton leak. This leak decreases the coupling of respiration to ADP phosphorylation,
and increases substrate oxidation and the dissipation of oxidation energy as heat. This process protects against hypothermia and
regulates energy balance. Both animal and plant mitochondria contain a group of mitochondrial carrier proteins known as the
uncoupling proteins (UCP). UCP1 is highly expressed by brown adipose tissue (BAT) — the main site for thermogenesis. The inner
membrane of BAT mitochondria have a high permeability to protons, due to the abundance of UCP1, so ATP production is
uncoupled, leading to heat production. Two mechanisms have been proposed by which UCP1 is able to transport protons. a | In the
first model, UCP1 transports protons (H+) and fatty acids (RCOO-). The fatty acid provides a free carboxyl group that makes proton
transport possible. The proton is then liberated from the fatty acid after it has crossed the membrane. b | In the second model, the
protonated form of the fatty acid diffuses freely across the membrane, and UCP1 transports the anionic form of the fatty acid
(RCOO-) back across to the other side.