CARNITINE

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CARNITINE

• Gamma-hydroxi-N-trimethylamino-butyrate

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• Sources of blood carnitine
• a.) mainly animal source food 1-8 , 300
  µmole/day
• b.) we synthesize in liver (brain, kidney) 1-2,
  100 µmoles/day
• c.) in kidney absorbed from the filtrate to the
  blood 92-98 (most important)
• Excretion
• - by urine 400 µmoles/day
• through gut changable amount
• Tissue content
• blood plasm 300 µmoles/5 liters, 40-60 µmoles/L
• skeletal muscle 2000-3000 µmoles/kg
• liver, heart 800-1500 µmoles/kg
• other tissues 600-700 µM
• all carnitine in tissues 50000 µmoles

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• Carnitine concentration is bigger in every cells
  than in blood, therefore the entrance is always
  active transport, the departure is passive.
• Carnitine is ionic (zwitter ion), so it requires
  in every membrane (plasma, mitochondria, ER) a
  protein transporter.
• Synthesis
• Last step is only in liver (brain and kidney
  insufficient amount).
• Starts from proteins, on Lys
• Localization of steps one after each other
  nucleus, lysosome, mitochondria, cytoplasm
• Requires SAM (Met), Lys, ascorbate, PLP, NAD,
  enzymes
• Vitamin or enzyme deficiency leads to improper
  synthesis, but food carnitine is enough.
• Strict vegetarian people can not eat high
  amount, but absorption from gut becomes more
  efficient.
• When carnitine transporter in the kidney does not
  function, carnitine is exreted by the urine,
  causing systemic carnitine deficiency in all the
  body.

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Lys és Met essencial amino acids
ascorbate
B6-vitamin l
B3-vitamin
the last step is sufficient only in liversmall
amount in brain,kidney
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Carnitine transporters in the membranes

• 1.) OCTN2 organic cation transporter(uniporter)
  high affinity carnitine/Na symporter Kt 1-6
  microMcarnitine reabsorption from the filtrate
  to the blood in the apical tubular cells in
  kidneycarnitine entrance from blood to cells
  skel. mucle, heart, pancreas, placenta, brain,
  lung, testis, fibroblastOCTN2 transporter
  protein hereditary deficiency leads to systemic
  carnitine deficiency
• 2.) OCTN3 intermediate affinity carnitine
  specific uniporter Kt 20 µMspermium, liver
  peroxisome
• 3.) OCT 1,2,3 intermediate affinity organic
  cation uniporters or exchangersbasal membrane of
  tubular cells in kidney, intestine, muscle, testis

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4.) OCTN1 low affinity organic cation/ H
antiporter Kt gt 500 µM in kidney proximal
tubules acyl-carnitines alkaloids, medicines
etc. are exreted to filtrate lung, bone
marrow, prostate, placenta, pancreas, heart,
uterus, spleen, testis... in mitochondrial
inner membrane 5.) ATBo, is a basic amino acid
uniporter Kt 0.8 mM lung, intestine, mammary
gland 6.) small affinity carnitine/Na symporter
high affinity gamma-butyrobetain/Na symporter
in liver, brain Carnitine is synthesized from
gamma-butyrobetain in one step.
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OCTN1
acyl-carnitine
carnitine
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Function of carnitine 1.) Entrance of LCFA (long
chain fatty acids) to mitochondria, ER,
peroxisome 2.) Leaving of SC(F)A short chain
acids from cell organells and cells to excrete
out of the cells and the body (as
acyl-carnitine). In case of OCTN2 hereditary
deficiency carnitine can not be reabsorbed from
filtrate, rather it is flowed out of the body,
causing systemic deficiency.
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Function of carnitine to transport fatty acids
into and out of cell organells
VLC very long chain CAC carnitine/acyl-carniti
ne translocase
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Signs of systemic carnitine deficiency

• Never nowhere fatty acids can enter to
  mitochondria to be oxidized, therefore
• always everywhere glucose (and amino acids) are
  degraded to yield energy, glucose is consumed
  very fast, causing between meals life
  threatening hypoglycemia, coma
• in liver, muscle etc. PDHC is not inhibited by
  acetyl-CoA (from FA oxidation) during fasting,
  glucose is not spared for obligate glucose
  consuming tissues

• No enough acetyl-CoA for citric acid cycle and
  activation of pyruvate carboxylase, gluconeogenes
  is does not proceed, glucose is not replenished.
• In starvation in liver no ketone body synthesis
  (from FA derived acetyl-CoA), so the brain can
  not gain them instead of glucose.
• Heart always oxidizes FAs, skeletal muscle uses
  FAs in resting and long term exercise. Without
  FA beta-oxidation no enough ATP for
  movement, causing tiredness, heart hyperthrophy,
  progressing cardiomyopathy, death of 2-4 years
  old child
• FAs can not enter to cell organells, they are
  accumulated in cytoplasm activating TAG
  synthesizing enzymes, causing lipid degeneration
  in liver, heart, muscle

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Therapy Big dose of oral carnitine during the
whole life for little affinity carnitine
transporters to work. 5 of normal concentration
in cells is enough.