Cholesterol 24-Hydroxylase: An Enzyme Turnover in the Brain

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Cholesterol 24-Hydroxylase: An Enzyme Turnover in the Brain

  1. 1. “Cholesterol 24-Hydroxylase: An Enzyme Turnover in the Brain" SPEAKER P.RAMESH Ph.D (Animal Biochemistry)
  2. 2. Introduction  Cholesterol 24-Hydroxylase is a member of Cytochrome- p450 family (~500 a.a)  Synonyms: Cytochrome P450 46A1, CP46, CYP46  Genes: Cyp46a1 (Mouse), CYP46A1 (Humans)  Catalysis: Conversion of Cholesterol into Oxysterols  Membranes of neurons in CNS (Brain & Spinal Cord)  Exclusively present in the Brain & small amounts in testis and liver of the mouse
  3. 3. Cont….  Responsible for majority of cholesterol turnover in the Vetebrate Central Nervous System  Expressed in neurons of hippocampal (learning), cortical neurons (memory)  Disruption of the gene in mouse reduces both cholesterol turnover and synthesis in the brain  No alteration in steady state levels of cholesterol in other tissues
  4. 4.  Brain is a metabolically active tissue Cont….  Occupies 2% of body mass in humans and tissue consumes 20% of resting oxygen  Burns an estimated 4x1021 molecules of ATP/min of the day  Mainly fueled by Glucose metabolism and on prolonged starvation, it depends on ketonebodies  Composed of lipids, including 20% of the body’s total cholesterol content
  5. 5. Cholesterol Levels in Tissues  Mouse Brain having cholesterol ~15mg/g tissue Adrenal gland ~19mg/g Lung ~6mg/g  Cholesterol in the Brain exists in two pools  One pool is largely containing ~70% (white matter), conc. ~40 mg/g tissue  Second pool is small having ~30% (gray matter), conc. ~8mg/g tissue
  6. 6. Cont…. Origin of Brain Cholesterol  Two sources: Exogenous (plasma lipoproteins) Endogenous (from Acetate)  High vascularized tissues, (adrenal gland and liver) have access to circulating lipoproteins (exogenous pathway)  Brain exclusively depends on endogenous pathway  Cholesterol is transported within the CNS in the form of apo-E from Glial cells
  7. 7. Fig:1 Blood-Brain barrier prevents exchange with plasma Cholesterol
  8. 8. Cholesterol metabolism in the Brain  Brain cholesterol located in myelin membranes of oligodendrocytes & small amount in PM of neurons  Cholesterol synthesis and accumulation as a function of Age dependent  Synthesis are increased during active myelination after birth  Cholesterol synthesis in the adult brain is larger than the accumulation rate
  9. 9. Cont….  Apo-E & membrane transporter of the ABC family are expressed in CNS  Apo-E containing lipoproteins from glial cells are bind to neuronal surface receptor & then uptake into it  Cholesterol 24-hydroxylase catalyzes conversion of cholesterol into 24s-hydroxycholesterol  Interplay between glial & neuronal cells  Regulates cholesterol homeostasis in brain
  10. 10. Cholesterol Turnover: Cont….  It also catalyzes 24,25 and 24,27-dihydroxycholesterols in brain & cerebrospinal fluid of mice & other mammals  Oxysterols is initially formed within the brain and then gain access to the circulation
  11. 11. Cont….  In plasma, it associates with lipoproteins, which are cleared by the liver  Mevalonate pathway (MP) synthesis cholesterol & nonsterol isoprenoids (Geranylgeraniol) responsible for learning  Lacking 24-hydroxylase excrete cholesterol more slowly & tissue compensates by suppressing Mevalonate pathway  Causes a severe deficiencies in spatial, associative, motor learning & hippocampal long-term potentiation (LTP)
  12. 12. Metabolism of 24s-hydroxycholesterol: Cont….  Having short half life & rapidly converted into Bile acids  Infants have high levels in the circulation  Cholesterol 7α & 7β-hydroxycholesterols hydryoxlates 24s- hydroxycholesterol and 24,25 and 24,27 hydroxy-cholesterol in the liver  In mouse CYP39 have a high 7αhydroxylase activity  24s-hydroxycholesterol is a less efficient precursor for bile acids than 7α- hydroxycholesterol  Half of it is conjugated and eliminated in bile as such or as a conjugate of a 27-OH cholesterol
  13. 13. Cont….  Functions: Atherosclerosis, Apoptosis, Necrosis, Inflammation, Immune suppression, Development of Gall- stones  Efficient suppressor of HMG-CoA reductase
  14. 14. Cont…. 24s-hydroxycholesterol as a marker:  Marker for neurological and neurodegenerative diseases  Brain-dead patients had a reduction in the conc. 50%  In Multiple sclerosis appear to have increased levels in the circulation  Alzheimer’s disease (AD) had significantly reduced plasma levels of the oxysterols  Patients with AD were found to have increased levels 24s-OH cholesterol in cerebrospinalfluid and parallel with decreased levels in circulation
  15. 15. Cont…. Cholesterol 27-hydroxylase (CYP27):  It is present in all most all cells in the body  Catalysis conversion of cholesterol into 27-OH cholesterol  27-OH cholesterol is further converted into 7α-hydroxy-3- oxo-4-cholestenoic acid by Cholesterol7β1-hydroxylase (CYP7β1) in glial cells  AD patients had increased levels of 27-OH cholesterol in brain  Alternatively for the high levels may be a reduced metabolism
  16. 16. Alzheimer’s Disease (AD):  It is neurological disease, characterized by death of neurons & even greater loss of synapses in the brain  Neurons death seems to be deposition of β-amyloid proteins  Neurons with reduced arborization have less surface area & corresponds less plasma membrane  Cholesterol catabolized through 2 main routes  Can be esterified & stored within neurons as a cholesterol esters  Oxidised at 24 or 27 to form 24-OHC & 27-OHC
  17. 17. Possible role of Oxysterols in AD: Cont….  CYP46A1 are expressed in neurons & some astrocytes in the normal brain  CYP27A1 present in oligodendrocytes & absent in neurons  In AD CYP46A1 shows prominent expression in astrocytes & around amyloid plaques  Invitro studies shows that 24s-OHC & 27-OHC inhibits β- amyloid proteins (Aβ)  Oxysterols also involved in signaling transduction pathway
  18. 18. Cont….  Oxysterols have dual function: Both are cholesterol catabolites Ligand of the nuclear transcription factor LXR  24-OHC levels high in plasma of patients of AD  Due to high levels its affect APP metabolism  Processing of APP by β & r-secretases produce Aβ, takes place in high cholesterol levels of lipid raft domains (Amyloid Protien Precursor)
  19. 19. Cont….  Cholesterol esters increase Aβ & inhibiting the LCAT reduces Aβ production  Synthetic Oxysterol 22-OHC inhibits Aβ production in some neuroblastoma cells  Oxysterols inhibits APP processing in neurons through a mechanism mediated by LXR  Activation of LXR system is known to increase ABC (ATPase binding cassette) levels
  20. 20. Summary & Conclusion  Cholesterol 24-hydroxylase is a highly conserved P450 that is expressed in some, but not all, neurons of the brain  Cholesterol 24-hydroxylase converts cholesterol, into 24S- hydroxy-cholesterol, that diffuses from the brain and is subsequently metabolized by the liver  Disruption of the mouse cholesterol 24-hydroxylase gene causes an ∼50% decrease in cholesterol turnover, which is compensated for by an equal decrease in the rate of de novo cholesterol synthesis
  21. 21. Cont….  Cholesterol 24-hydroxylase knockout mice are deficient in spatial, associative, and motor learning, and have abnormal hippocampal LTP  The defect in LTP can be reversed by geranylgeraniol, a poly- isoprenoid end product of the cholesterol biosynthetic pathway
  22. 22. Future Issues  What role does cholesterol turnover play in the human brain?  Are there naturally occurring mutations in the human cholesterol 24-hydroxylase gene, and if so, what are their clinical consequences?  What other pathways exist for cholesterol catabolism in the central nervous system?  Are these pathways present in the peripheral nervous system?  What transport processes bring cholesterol to the enzyme in the endoplasmic reticulum membrane?
  23. 23. Fig:
  24. 24. Fig: Synthesis of A)24-hydroxy-cholesterol &B) cholesterol
  25. 25. Fig: Interaction between Astrocytes (glial cells) and Neuronal cells in Cholesterol Homeostatsis in the Brain
  26. 26. Fig: Flux of 24s-hydroxycholesterol from the Brain

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