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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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 from cells of
lung, bone marrow, protate, placenta, pancreas,
heart, uterus, spleen, testis... to blood 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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• 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.
• 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

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• 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 etc.
• 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.