Transcript L-Carnitine in human metabolism

L-Carnitine in human metabolism
L-Carnitine Clinical Pharmacology (I)
• L-Carnitine is a natural substance essential for our energy metabolism.
• L-Carnitine brings long-chain fatty acids into mitochondria for oxidation
and energy production.
• Fatty acids are the energy substrates for all tissues except the brain.
• In cardiac and skeletal muscle, fatty acids provide the main energy
production.
SPC L-Carnitine Oral Solution China
L-Carnitine is a natural substance!
25% L-carnitine is synthesized from amino acid lysine and
methionine mostly in our liver and kidney.
75% L-carnitine comes from our diet.
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L-Carnitine is present all-over our body!
Tissue /
Body Fluids
L-Carnitine
Content
nmol/g
Muscle
1.100 – 3.900
Heart
600 – 1.200
Liver
600 – 1.000
Kidney
300 – 600
Brain
500 – 1.000
Blood
40 – 60
Carnitine/Acylcarnitines in our fluids
Plasma free carnitine (FC) is in
dynamic balance with acylcarnitines
(AC) with the acyl to free Carnitine
ratio of ≤ 0.4 being considered
normal.
Carnitine deficiency
 FC< 20 micromol/L
 AC/FC > 0,4
Cellular Carnitine System
Enzymes and Proteins
L-Carnitine: Mechanism of Action
The essential roles of Carnitine
• Fatty acid transport and oxidation with energy production
• Detoxification of «toxic» metabolites
• Stabilization of cell membranes & prevention of apoptosis
• Regulation of the mitochondrial acyl-CoA/CoA ratio
The essential roles of Carnitine
• Fatty acid transport and oxidation with energy production
• Detoxification of toxic metabolites
• Stabilization of cell membranes & prevention of apoptosis
• Regulation of the mitochondrial acyl-CoA/CoA ratio
Long Chain Fatty Acids Transport & Oxidation
Carnitine is the only transporter.
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Acyl-CoA-Synthetase
Long-chain fatty acids (>12 C) are extracted from triglycerides by an
intracellular lipase. Fatty acids are then activated by Acyl-CoA
Synthetase, located in the outer mitochondrial membrane.
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Carnitine Palmitoyl-Transferase I (CPTI)
Carnitine
The Carnitine Palmitoyl - Transferase I (CPTI)
transfers the acyl group from activated fatty acid (acyl-CoA) to carnitine, forming
acylcarnitine and releasing CoA in cytoplasm
Acyl-CoA
Acyl CoA + L-carnitine
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CPT I
CoA + Acyl-L-carnitine
Carnitine Translocase
The Carnitine–acylcarnitine translocase
carries a molecule of acylcarnitine from the cytosol to the mitochondrion
exchanging it with one molecule of free carnitine present in the mitochondrion,
that is transported in the cytosol.
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Carnitine Palmitoyl-Transferase II
The Carnitine Palmitoyl - Transferase II (CPT II)
is located on the inner side of mitochondrial matrix. It converts acylcarnitine
in acyl-CoA and L-Carnitine.
Acyl-carnitine + CoA
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CPT II
Acyl-CoA + L-carnitine
Energy production
Finally the acyl-CoA is conveyed to the betaoxidation and fragmented in chains
containing two Carbons (acetyl-CoA), which
subsequently enter in the Krebs cycle, the
Electron Transport Chain, with the final
result of energy production (ATP).
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L-Carnitine: Mechanism of Action
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Fatty acids are fundamental for energy!
Energy content of biomolecules
Percentage of body substance
Burning power
(kcal/g)
(kcal/
Brennwert
gramm)
12
%
%
10,5
15
61
Proteins
14
20
35
Carbohydrates
0,7
1
2
Minerals
3,5
5
—
Water
42
58
—
Fat
8
KohlenCarbo
hydrates
hydrat
4
0
Protein
Proteins
Alkohol
Alcohol
Energy
kg
Erdöl
Petrol
Fett
Fat
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Mass
Fatty acids are fundamental for energy!
Energy content of biomolecules
Percentage of body substance
Burning power
(kcal/g)
(kcal/
Brennwert
gramm)
12
Erdöl
Petrol
Fett
Fat
Carbohydrates
0.59%
Proteins
14.46%
8
KohlenCarbo
hydrates
hydrat
Lipids
(triglycerides)
84.95%
4
0
Protein
Proteins
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Alkohol
Alcohol
Metabolic Pathways
Carbohydrates
Glucose
Glucose-1phosphate
Glycogenesis
Glycogen
Glycogenolysis
Glyceraldehyde3-phosphate
Lipogenolysis
Glycerol
TGs
Lipogenesis
Pyruate
Lipolysis
Fatty Acids
β-oxidation
Protein
Amino
acids
Acelyl CoA
Lipogenesis
Glyconeogenesis
Urine
Urea
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Kreb’s
(TCA)
Cycle
(amino
acids)
NH3
Urea
Cycle
FAs
ATP
Ketone bodies
Acetoacetate
Acetone
β-Hydroxbutyrate
NH3 = Ammonia, generated by metabolism in all organs
Fas = fatty acids
TGs = tryglycerides
Muscles & Blood Pressure
Short-term mechanisms include both (1) neural and (2) hormonal controls, which alter blood pressure by changing peripheral resistance and CO
Fatty acid metabolism & carnitine
Zhang et al., Biochimica et Biophysica Acta 1801 (2010)
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Growth Velocity & Basal Metabolic Rate
Son’kin and Tambovtseva (2012). Energy Metabolism in Children and Adolescents, Bioenergetics, Dr Kevin Clark (Ed.),
ml/kg/min
Fatty acid oxidation is the highest in children
hours
Oxygen consumption and carbon dioxide production for each group during the background hood day.
Symbols (Triangle = child VO2, Diamond = child VCO2,
Square = adult VO2, Circle = adult VCO2).
Values are means ± SE
Kostyak JC et al (2007) Nutrition Journal, 6:19
L-carnitine plays a key role in metabolism
• L-Carnitine is crucial and exclusive for long chain fatty acid
metabolism/oxidation
• Fatty acid oxidation is fundamental part of metabolic pathways
• The metabolic pathways link the main vital organs and tissues
• L-Carnitine is strictly linked to the metabolic pathways of main
vital organ and tissues
Carnitine transport across the plasma and
mitochondrial membranes
Saini-Chohan et al, Journal of Lipid Research 2012. 53: 4–27
Fatty Acid Toxicity & Carnitine Deficiency
Zhang et al., Biochimica et Biophysica Acta 1801 (2010)
The carnitine cycle in fatty acid oxidation
Longo N at al, Am J Med Genet C Semin Med Genet 142C(2) (2006) 77–85
L-Carnitine & metabolism
Genetic
background
Food intake
excess
Physical
inactivity
Obesity
Hyperglycemia
Hyperinsulinemia
Dyslipidemia
Insulin
Inflammation
Hypertension
resistance
Hypercoagulation
Atherosclerosis- Heart Failure
Adapted from Mate A et al. . 2010; Drug Discovery Today 15, Number 11/12.
Fatty Acid Oxidation & the Heart
Lionetti et al., Cardiovascular Research (2011) 90, 202-209
L-carnitine on Heart Metabolism
L-CARNITINE
FATTY ACIDS OXIDATION
GLUCOSE METABOLISM
PYRUVATE
LONG-CHAIN
ACYL-CARNITINE
LONG-CHAIN FATTY-ACIDS
PROTECTION OF LIPID MEMBRANES
AND PROTEIN ENZYMES
ATP
DE-INHIBITION OF ATP-ase
IN SARCOLEMMA
COMPLIANCE
CONTRACTILITY
NECROTIC AREA
Lango R at al, Cardiovascular Research 51 (2001) 21–29
RESTORING OF REST-POTENTIAL
VENTRICULAR ARRHYTHMIA
Systemic Primary Carnitine Deficiency CDSP:
Childhood myopathic (cardiac) presentation
Chest radiographs
A) 4 years with a heart size upper
limits of normal.
B) 6.5 years severe cardiomegaly,
and low plasma total carnitine
(1.0 nmol/mL)
C) the cardiac size decreased to
normal by six months of oral LC
treatment (100 mg/Kg/day)
D) 10.5 years the cardiac size
remained normal for more than 5
years with LC therapy.
Pierpont 2000
Myocardial histology and immunohistochemistry in
Primary Carnitine Deficiency
Myocardial biopsy shows boxcar nuclei and vacuoles (A; arrows), positive Oil Red O staining for intramyocardial lipid accumulation (B; arrow) and enlarged,
swollen mitochondria seen with electron microscopy (C, D; arrows). Immunohistochemistry with antibodies directed against aldehyde 4-hydroxy-2-nonenal 4HNE (E , F) and sarcoendoplasmic reticulum calcium ATPase SERCA-SO 3 shows increased staining (F, H) compared to normal controls ( E, G)
Mazzini M at al, Cardiology 120 (2011) 52–58
Primary Carnitine Deficiency
ECGs obtained during the initial hospitalization ( left )
and after 6 months of treatment with carnitine ( right).
The initial findings of inferolateral early repolarization
and increased voltage resolved
Mazzini M at al, Cardiology 120 (2011) 52–58
Fatty Liver Caused by Carnitine Deficiency
Limketkai BN at al, J Gen Intern Med Med. 2007; 23(2): 210-13
Hyperammonemic Encephalopathy Caused by
Carnitine Deficiency
Limketkai BN at al, J Gen Intern Med Med. 2007; 23(2): 210-13
The essential roles of Carnitine
• Fatty acid transport and oxidation with energy production
• Detoxification of «toxic» metabolites
• Stabilization of cell membranes & prevention of apoptosis
• Regulation of the mitochondrial acyl-CoA/CoA ratio
Detoxification of toxic metabolites
If long chain fatty acids accumulate and
become cytotoxic by degrading cellular
membranes and inhibiying enzymes.
Detoxification of toxic metabolites
Toxic organic acids
Toxic organic acids accumulate and
become cytotoxic by degrading cellular
membranes and inhibiying enzymes and
also induce acidosis.
Metabolic Findings in Organic Acidemias
Caused by Abnormal Amino Acid Catabolism
Disorder
Propionic acidemia
Amino Acid
Pathway(s) Affected
Isoleucine, valine,
methionine, threonine
Enzyme
Diagnostic Analytes by GC/MS 1 and
Quantitative Amino Acid Analysis
Propionyl CoA
carboxylase
Propionic acid, 3-OH propionic acid, methyl
citric acid, propionyl glycine in urine
Propionylcarnitine, increased glycine in
blood
Methylmalonic acidemia
(MMA)
Isoleucine, valine,
methionine, threonine
Methylmalonyl
CoA mutase
Methylmalonic acid in blood and urine
Propionic acid, 3-OH propionic acid, methyl
citrate in urine
Acylcarnitines, increased glycine in blood
Glutaricacidemia type I -GA I
Lysine, hydroxylysine,
tryptophan
Glutaryl CoA
dehydrogenase
Glutaric acid, 3-OH-glutaric acid in urine
Glutarylcarnitine in blood
1. Gas chromatography/mass spectrometry
Detoxification of toxic metabolites
Valproic Acid (VPA)
Lheureux 2009
The essential roles of Carnitine
• Fatty acid transport and oxidation with energy production
• Detoxification of «toxic» metabolites
• Stabilization of cell membranes & prevention of apoptosis
• Regulation of the mitochondrial acyl-CoA/CoA ratio
The essential roles of Carnitine
• Fatty acid transport and oxidation with energy production
• Detoxification of «toxic» metabolites
• Stabilization of cell membranes & prevention of apoptosis
• Regulation of the mitochondrial acyl-CoA/CoA ratio
Stabilization of cell membranes
Carnitine has a stabilizing effect on cell membranes, regulates the
turnover of damaged fatty acids within the phospholipid (PLP)
membranes (ie, after oxidative stress insult). PLA2= phospholipase A2
L-Carnitine Stabilizes cell membranes
Morphological alterations of cup-to-eye.
Control retinal samples (1); methylcellulose treated retinas in
the presence (2); or absence of carnitine (3). Magnification
was × 500 in all cases
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Calandrella et al., Cell Death and Disease (2010) 1, e62
L-Carnitine prevents apoptosis
malondialdehyde (MDA). Mtc,
methylcellulose; Carn, L-carnitine.
(b) increase of the intraocular
pressure (IOP) results in oxidative
stress as shown by the
overexpression of inducible nitric
oxide synthase (iNOS).
Mitochondrial lipid peroxidation
causes the accumulation of
intracellular MDA: a hallmark of
lipoperoxidation. The activation of
the ubiquitin (Ub)-mediated
proteasome pathway is directly
related to the execution of the
apoptotic death as also shown by
the stimulation of caspase 3
expression.
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Calandrella et al., Cell Death and Disease (2010) 1, e62
Very low Carnitine in newborns developing T1D:
loss of antiapoptotic activity
Total carnitine
Free carnitine
La Marca Nutrition & Diabetes (2013) 3, e94
Acyl-carnitine
The essential roles of Carnitine
• Fatty acid transport and oxidation with energy production
• Detoxification of «toxic» metabolites
• Stabilization of cell membranes & prevention of apoptosis
• Regulation of the mitochondrial acyl-CoA/CoA ratio
The essential roles of Carnitine
• Fatty acid transport and oxidation with energy production
• Detoxification of «toxic» metabolites
• Stabilization of cell membranes & prevention of apoptosis
• Regulation of the mitochondrial acyl-CoA/CoA ratio
Regulation of the mitochondrial
Acyl-CoA/ CoA ratio
• Free CoA is an essential element in the cell’s metabolic pathsways, cell membranes
are impermeable to CoA.
• Carnitine controls intracellular/intramitochondrial concentrations of acyl-CoA and
free CoA.
Acyl CoA + L-carnitine
CoA + Acyl-Lcarnitine
Free CoA regulates mitochondrial key-enzymes
(pyruvate dehydrogenase and beta-oxidation dehydrogenases), which
control lipid and glucose metabolism.
Mitochondrial carnitine pathway
interplay between fatty acid and glucose metabolism
L-carnitine plays a key role in metabolism
• L-Carnitine
is
crucial
metabolism/oxidation
and
exclusive
for
fatty
acid
• Fatty acid oxidation is fundamental part of metabolic pathways
• The metabolic pathways link the main vital organs and tissues
• L-Carnitine is strictly linked to the metabolic pathways of main
vital organ and tissues
• Carnitine deficiency induces derangement of the metabolic
pathways with impairment of the vital organs and tissues
Oral L-Carnitine Indications
Chronic treatment of primary (and secondary carnitine deficiency).
Main clinical presentations:
•
•
•
•
•
•
cardio - myopathy
hypotonia
muscle weakness
hypoketotic hypoglycemia
failure to thrive
recurrent episodes of Reye-like encephalopathy
The recommended dosage of Levocarnitine Oral Solution is:
• 50 to 100 mg/kg/day equivalent to 0.5 to 1mL/kg/day T.I.D (three times
a day)
• to be increased to a maximum of 3/day (30 mL/day)
Thank you