Advanced lipoxidation end products ALE

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Advanced lipoxidation end products (ALE)

• Ardalan Barghi, Max LaFontaine, Pascal Niccoli

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What are ALE?

• Advanced Lipoxidation Endproducts
• Proteins which have been irreversibly modified by
  reactive carbonyl compounds (e.g.
  Malondialdehyde)
• The modification is non-enzymatic
• Closely related to Advanced Glycation
  Endproducts, in that both are irreversibly
  modified protein, one is modified by
  glucose/carbohydrates (AGE) and the other by
  lipids (ALE)

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ALE formation
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Reactive Carbonyl Compounds

• Reactive Carbonyl Compounds (RCC) also play a
  role in ALE generation by reacting with protein
  amino groups
• RCC are continuously generated as side products
  of lipid peroxidation reactions due to oxidative
  stress

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Reactive Carbonyl Compounds
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ALE Who is at risk

• Elderly (ALE formation is a part of the aging
  process, ALE accumulation in collagen decreased
  elasticity)
• Diabetes (Glucose levels uncontrolled)
• Uremic disorder
• Diet high in ALE (Heated, Irradiated or Ionized
  food)

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ALE Why they are harmful

• ALE highly correlated with chronic diseases
• ALE, when accumulated in the body, will Increase
  inflammation in the body, reduce antioxidant
  defense, weaken the immune system , impair DNA
  repair mechanisms and increase the rate of
  infection

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ALE and Allergies

• Thermal processing of foods (heating/roasting)
  can often introduce neo-antigens and increase
  allergenicity
• E.g. Roasting peanuts is reported to
  significantly increase the amount of ALE which
  ultimately can affect IgE binding.

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ALE and Atherosclerosis

• One of the best-known effects of ALE precursors
• ALEs modify LDLs
• LDL oxidation occurs by contact with ROS,
  generating lipid peroxidation products
• These products react with the Lys residues of
  apoB, which recognize LDL by its specific apoB/E
  receptor
• Therefore, LDL modification alters its affinity
  for the apoB/E receptor and its metabolism is
  performed only by macrophages, which form foam
  cells

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ALE and Atherosclerosis (contd)

• accumulation of foam cells leads to the formation
  of atherosclerotic lesions
• LDL modifications by ALE have been detected in
  the plasma of diabetics
• diabetic cataracts are associated with increased
  deposition of ALE-modified proteins in the lens
• 4-HNE accumulation may contribute to the
  mechanisms of obesity and insulin resistance

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(No Transcript)
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ALE and neurodegenerative disorders

• Proteasomes are generally activated by oxidative
  stress, however HNE-modified proteins may inhibit
  proteolytic activity
• modification of proteins by 4-HNE leads to
  protein aggregates that accumulate in cells
• Accumulation of cross-linked proteins can lead to
  diseases such as Alzheimer's disease
• accumulation of modified proteins may also
  inhibit neuronal cells
• Response is characterized by an upregulation of
  COX-2 and PGE2, which contributes to
  neurodegeneration

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ALE and neurodegenerative disorders

• 4-HNE impairs mitochondrial function by altering
  GSH metabolism, causing mitochondrial oxidative
  stress. 
• In Parkinson's disease, the oxidative stress
  contributes to mitochondrial dysfunction and
  degeneration of dopaminergic cells
• 4-HNE is generated in brains of human patients
  affected with CreutzfeldtJakob disease but their
  role in the progression of the disease is not
  known

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ALE and Cancer

• HNE itself is carcinogenic for hepatocytes,
  triggering proliferative and inflammatory
  responses, which could play a role in tumour
  growth
• Also potentially involved in the promotion of
  colon cancer carcinogenesis 

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Treatment Options

• Hydrazine Forms DNPH (hydrazine derivative),
  which prevents the formation and the accumulation
  of acrolein and 4-HNE adducts on cellular
  proteins.
• Hydralazine traps aldehyde-adducted proteins as
  well as reverses the formation of 4-HNE and
  acrolein adducts on tissue, inhibits the
  modification of LDL and is a powerful
  antioxidant.

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Treatment Options (contd)

• Vitamin B6 exhibits antioxidant properties as it
  participates in the maintenance of reduced GSH,
  which is a major antioxidant and a natural ALE
  precursor scavenger.
• ACE inhibitors exhibit antioxidant properties and
  block LDL oxidation, lipid peroxidation and the
  generation of MDA and 4-HNE

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Treatment Options (contd)

• Antioxidants prevent lipid peroxidation, and thus
  the formation of ALEs on proteins. Pretreatment
  of neurons with high concentrations of
  antioxidants prevents 4-HNE-induced neuronal
  death.
• Resveratrol a red wine polyphenol, exhibits
  protective properties against lipid peroxidation
  and ALE formation in experimental models for
  numerous diseases including atherosclerosis,
  diabetes and Alzheimer diseases.

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Summary

• Lipid peroxidation is induced by oxidants and
  oxidative stress, generates a huge variety of
  lipid peroxidation products, including Reactive
  Carbonyl Compounds (RCCs) and more stable
  products such as ketones and alkanes
• These products react on cellular proteins to form
  complexes known as Advanced Lipoxidation
  Endproducts (ALEs)
• ALEs can cause protein dysfunctions and alter
  cellular responses. 

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Summary (contd)

• ALEs can cause atherosclerosis,
  neurodegenerative disorders (Alzheimers,
  Parkinsons, Creutzfeldt-Jakob), Allergies
• Can be treated with Hydrazine, Hydralazine,
  Vitamin B6, ACE inhibitors, Resveratrol

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References

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  R, Milzani A, Carini M (2006). Lipoxidation-derive
  d reactive carbonyl species as potential drug
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• Brown MS, Goldstein JL (1983). Lipoprotein
  metabolism in the macrophage implications for
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  Rev Biochem 52 223261
• Leonarduzzi G, Chiarpotto E, Biasi F, Poli G
  (2005). 4-Hydroxynonenal and cholesterol
  oxidation products in atherosclerosis. Mol Nutr
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• Zang M, Xu S, Maitland-Toolan KA, Zuccollo A, Hou
  X, Jiang B et al. (2006). Polyphenols stimulate
  AMP-activated protein kinase, lower lipids, and
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