role of liver in metabolism...carbohydrate metabolism and the liver • low blood glucose level...
TRANSCRIPT
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Role of liver in metabolismRole of liver in metabolism
LIVEREmployee of the month
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Functions•
Central role in metabolic regulation and the
energy transfer•
Biosynthesis: glucose, plasma proteins
•
Storage: glycogen, metal ions, vitamins•
Detoxification: biotransformation, urea‐cycle,
bile product
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Carbohydrate metabolism and the liver
•
Low blood glucose levelactivation of glycogenolysis and
gluconeogenesis
•
High blood glucose levelactivation of glycogenesis and
glycolysis
‐
Excess
glucose: acetyl‐CoA‐>FFA‐>TG•
HMP‐shunt
•
Cori‐cycle and
glucose‐alanine cycle
FFA: free fatty acid TG: triglyceride
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Liver specific processes in carbohydrate metabolism
•
Glycolysis: glucokinase isoenzyme•
Gluconeogenesis: glucose‐6‐phosphatase
•
Fructose metabolism•
Galactose metabolism
•
Synthesis of uron acids (glucuronic acid)‐
Conjugation processes
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Lipid metabolism and liver•
Regulation of blood free fatty acid concentration:
synthesis of TG•
Synthesis of cholesterol and lipoporotein
metabolism
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Liver specific processes in lipid metabolism
•
Synthesis of ketone bodies (acetone, acetoacetic acid, beta‐hydroxybutyric‐acid)
‐
Alternative energy source‐
Ketone bodies are produced from acetyl‐CoA
‐
Use: brain, heart, sceletal muscle‐
Metabolic acidosis, osmotic diuresis
acetoneacetoacetic acidB‐hydroxybutyric‐acid
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Liver specific processes in lipid metabolism
•
Synthesis of bile acids:‐
primary ~: cholic acid, chenodeoxycholic acid
secondary ~: deoxycholic acid, lithocholic acid‐
Enterohepatic circulation (later)
‐
Functions: 1.Fat digestion (emulsification)2.Cholesterol elimination
conjugationwith taurine or glycine
Bile: Aqueous solution containing bile acids (80%), cholesterol (5%), phospholipids (15%), bile pigments, inorganic and other materials.
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Protein metabolism and liver
•
After the absorption, amino acids are transported to the liver
•
Synthesis of plasma proteins (exception: Ig)•
Synthesis of coagulation factors
•
Synthesis of acute phase proteins•
Synthesis of non essential amino acids
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Liver specific processes in protein metabolism
•
Protein metabolism end product: ammonia‐
Elimination: Urea cycle
def.: hyperammonemia
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Bilirubin metabolism
•
Hemoglobin‐>biliverdin‐>bilirubin‐> transfer to liver by albumin: unconjugated=indirect bilirubin
•
Conjugation with glucuronic acid in liver (UDP‐ glucuronyl‐transferase): conjugated=direct bilirubin
•
It goes into the bile and thus out into the small intestine and passes into the
colon
•
Colonic bacteria deconjugate and metabolize the bilirubin: formed urobilinogen
and stercobilinogen
•
Szterkobilinogen‐>stercobilin: brown color of stool•
Urobilinogen is resorbed (enterohepatic circulation)
‐>urobilin: yellow color of urine
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Bilirubin metabolism
Conjugation of bilirubin(=Unconjugated)
(=Conjugate
d)
UDP‐glucuronyl‐
transferase
transporter
Blood
Organic‐anion‐
transporter
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Disease: Icterus=Jaundice
•
Icterus=hyperbilirubinemia: serum bilirubin >35mol/l (ref. <17 µmol/l)
•
Yellow pigmentation of the skin, sclera and other mucous membranes
•
Types: Serum indirect bilirubin
Serumdirect
bilirubin
Urinedirect
bilirubin
Urine UBG
Prehepatic ++ 0 0 +(n)
Hepatic + + + ++
Posthepatic 0 + ++ 0
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•
Prehepatic icterus:‐
unconjugated bilirubin
‐
main cause: hemolysis
•
Hepatic icterus:‐
conjugated and unconjugated bilirubin
(conjugated bilirubin >50%)
‐
main cause: liver failure
•
Posthepatic icterus:‐
conjugated bilirubin
‐
main cause: obstruction of bile duct
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Genetic hyperbilirubinemia
•
Unconjugated hyperbilirubinemia:‐
Gilbert‐disease: defect of UDP‐glucuronyl‐
transferase (gtriggers: alcohol, stress)‐
Crigler‐Najjar sy: defect of UDP‐glucuronyl‐
transferase
•
Conjugated hyperbilirubinemia:‐
Dubin‐Johnson sy: mutation of MRP2 protein
‐
Rotor sy:
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Biotransformation and alcohol breakdown
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Biotransformation
•
Functions:1. Detoxification: nonpolar compounds polar
compounds‐
Exogenic and endogenic materials
2. Synthesis and inactivation of signaling molecules
•
Localisation: liver•
3 phases
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Phase I: Preparation•
Add functional groups(‐COOH, ‐SH, ‐OH, ‐NH2
)‐
hydrolysis
‐
reduction‐
oxidation: Microsomial respiratory chain:
‐>NADPH‐cytochrome P450‐reductase
‐>Cytochrome b5‐>Cytochrome
P450
isoenzymes
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Phase II: Conjugation•
Conjugation with endogenous molecules
(glucuronic acid, glutathione, amino acid)‐> large increase in hydrophilicity
‐
glucuronidation (UDP –glucuronil‐transferase)
‐
sulphatation (PAPS)‐
methylation (SAM)
Glucuronidation
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Phase III: Transport
•
The resulting compounds transported to blood or bile by different transporters (active
transport)‐
ABC transporter
‐
P‐type ATPase
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Regulation of biotransformation•
Enzyme induction: only microsomal enzyme
system‐
endogenous inductor: hormones (after birth)
‐
exogenous inductor: drugs (antibiotics, dioxin) ‐
the inductors induced cofactor supply
•
Cofactors: nessecery in phase I and II‐
Phase I.: NADPH (oxygenase system)
‐
Phase II: UDP‐glucuronic acid (glucuronidation)
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Pathological conditions
•
Non toxic materialstoxic materials‐
Nitrose amine
diaso‐hidroxide –> mutagenic
•
Enzyme defects‐
pl.: Gilbert‐disease, Dubin‐Johnson syndrome
CYP2E
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Alcohol metabolism
•
Drug without receptor•
Sympathetic tone ↑
(adrenalin ↑)
•
Rapid absorption from the gastrointestinal system
•
Metabolism:‐
1‐5 mmol/l blood concentration: alcohol‐
dehydrogenase‐
>5 mmol/l: microsomical ethanol oxidizing system
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First metabolism (FPM)•
In stomach
•
10‐20%•
High alcohol concentration
•
Alcohol‐DH: Km>500 mM
•
FPM(first pass metabolism) ↓:‐
starvation
‐
inhibiting alcohol‐DH‐
low FPM: female
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Secondary metabolism•
In LIVER!!!
ADH: alcohol‐DHALDH: aldehyde‐DH
CYP2E1: microsomical ethanol oxidizing system
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Effect of alcohol•
NADH/NAD ration ↑
(NADH↑):
‐
Inhibition of fatty acid oxidation‐>TG↑-> fatty liver
‐
Inhibition of gluconeogenesis ‐> starvation hypoglycemia
‐
Inhibition of TCA cycle‐
acetyl‐CoA↑
NADH↑ NADH
↑ethanol acetaldehyde acetic acid
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Alcohol’s damaging effects•
Production of Reactive Oxygen Species ↑
:
‐
Mithocondrial respiratory chain ‐>oxygen free radicals↑
‐
Lipid peroxidation and protein oxidation‐
Elevation of intracellular free iron levels‐> oxygen
free radicals ↑‐
Mitochondrial damage ‐>ATP production↓
‐
Activation of CYP2E1 enzyme system‐> oxygen free radicals ↑
‐
Xantin dehydrogenase → xantin oxidase ↑
(superoxide radicals ↑)
‐
Antioxidant enzymes and glutathione ↓
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Effect of chronic alcohol consumptionNADH↑
d TG↑
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Alcohol’s effects on the different organsOrgan Condition EffectCentral nerve system Acute confusion → coma
Chronic Memory disfuntcion, psychosis
Distraction Attack, delirium tremens
Cardiovascular system Chronic CardiomyopathySceletal muscle Chronic MyopathyGastric mucosa Acute Irritation
Chronic Ulcer
Liver Chronic Fatty liver → cirrhosisKidney Acute diuresisBlood Chronic Anemia, decrease of plateletsTestes Chronic ImpotenceFetus Pregnancy Foetal alcohol syndrome