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62 Cards in this Set
- Front
- Back
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Carnitine Deficiencies characterized by...
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hypoglycemic, hepatosplenomegaly from buildup of fatty acids, NO ENERGY, fatty acids build up.
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FAO takes place in...except for
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mitochondria with help of carnitine, except for LCFA, these can be oxidized in the cytosol
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FAS takes place in the
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cytosol with citrate malate shuttle
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carinitine made in...exported to...
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carnitine made in the liver and kindeys, exported to other tissues
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FAO steps and key enzymes
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Once inside mitochondria, ready for oxidation. 2 carbons at a time, via acyl-dehydrogenases
Making of acetyl CoA, releasing ATP. Oxidation, hydration, oxidation, thiolysis Via thiolase last step Acetyl CoA can then be used for gluconeogenesis when combined with OAA ORRR KB synthesis |
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carnitine inhibited by
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INSULIN because carninte is active during FASTED state, insulin during FED state
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CPT-1 Deficiency
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- Affects the liver (liver isoform)
- Reduced fatty acid oxidation - Hypoketotic • Low blood ketone body levels • No acetyl coA to make KB • Fatty acids are stuck in the tissues!! Cannot be mobilized for FAO - Hypoglycemic • NEFA’s cannot be oxidized, therefore energy required for gluconeogenesis is not produced - DEATH SOON AFTER BIRTH! |
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CPT2 Deficiency
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- Reduced fatty oxidation in skeletal and cardiac muscles
- Cardiomyopathy in severe cases - Muscle cramps following prolonged exercise - Myoglobinuria (Brown urine) - High carb, low fat diet and avoid fasting |
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Translocase Deficiency
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- Making acyl-carnitine, but cannot get it to mitochondrial matrix
- Very rare, very lethal - Muscle weakness, hypoglycemia, hyperammonaemic & cardiomyopathy |
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Primary Carnitine Deficiency
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- Defective OCTN-2 (carnitine transport – brings carnitine from the serum into cytosol) causes failure of import of carnitine into extrahepatic tissue
- Low intracellular carnitine levels - Low plasma carnitine levels - Kidneys fail to re-absorb it from the filtrate because they themselves are not getting enough ATP |
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Carnitine Deficiencies characterized by...
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hypoglycemic, hepatosplenomegaly from buildup of fatty acids, NO ENERGY, fatty acids build up.
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FAO takes place in...except for
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mitochondria with help of carnitine, except for LCFA, these can be oxidized in the cytosol
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FAS takes place in the
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cytosol with citrate malate shuttle
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carinitine made in...exported to...
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carnitine made in the liver and kindeys, exported to other tissues
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FAO steps and key enzymes
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Once inside mitochondria, ready for oxidation. 2 carbons at a time, via acyl-dehydrogenases
Making of acetyl CoA, releasing ATP. Oxidation, hydration, oxidation, thiolysis Via thiolase last step Acetyl CoA can then be used for gluconeogenesis when combined with OAA ORRR KB synthesis |
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carnitine inhibited by
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INSULIN because carninte is active during FASTED state, insulin during FED state
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CPT-1 Deficiency
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- Affects the liver (liver isoform)
- Reduced fatty acid oxidation - Hypoketotic • Low blood ketone body levels • No acetyl coA to make KB • Fatty acids are stuck in the tissues!! Cannot be mobilized for FAO - Hypoglycemic • NEFA’s cannot be oxidized, therefore energy required for gluconeogenesis is not produced - DEATH SOON AFTER BIRTH! |
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CPT2 Deficiency
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- Reduced fatty oxidation in skeletal and cardiac muscles
- Cardiomyopathy in severe cases - Muscle cramps following prolonged exercise - Myoglobinuria (Brown urine) - High carb, low fat diet and avoid fasting |
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Translocase Deficiency
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- Making acyl-carnitine, but cannot get it to mitochondrial matrix
- Very rare, very lethal - Muscle weakness, hypoglycemia, hyperammonaemic & cardiomyopathy |
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Primary Carnitine Deficiency
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- Defective OCTN-2 (carnitine transport – brings carnitine from the serum into cytosol) causes failure of import of carnitine into extrahepatic tissue
- Low intracellular carnitine levels - Low plasma carnitine levels - Kidneys fail to re-absorb it from the filtrate because they themselves are not getting enough ATP |
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- Myopathic
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• Affects only the muscle
• LIVER UNAFFECTED |
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- Systemic
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• Affects multiple tissues
• Will effect the liver, so the liver wont be able to transport this back to the cardiac and muscle tissues • So many tissues will be affected |
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treatment for some of these carnitine deficiences
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Exploit a short and medium chain fatty acid diet as these don’t require carnitine
• Dietary carnitine therapy raises carnitine blood levels, forcing carnitine into cells |
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Medium Chain Fatty Acyl-CoA Dehydrogenase Deficiency (MCAD
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- Most common form of genetic defect in lipid disorder
- Deficiency in medium chain acyl-CoA dehydrogenases - Autosomal recessive disorder - Only partial production of energy because - Decreased ability to oxidize fatty acids with 6-10 carbons - Severe hypoglycema bc tissues increase reliance on glucose but no energy there to utilize gluconeogenesis - MCFA detected in the urine - Hepatomegaly - 10% of SIDS cases linked with this - Tx: avoid fasting o SCFA and LCFA dehydrogenase deficiencies have also been reported and have similar symptoms |
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Jamaican Vomiting Sickness (TOXINS)
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- Unripe fruit of akee tree with rare amino acid hypoglycin
- Hypoglycin metabolism produced MCPA-CoA - MCPA-CoA is IRREVERSIBLE INHIBITOR of SCFA and LCFA dehydrogenases - Hypoglycemia bc glucose major energy source - Vomiting, convulsions, metabolic coma |
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Defiency in B12
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methylmalonyl CoA mutase defiency= HIGH concentration of methylmalonyl CoA in the blood
Metheylmalonyl CoANOT going to succinyl CoA |
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Acyl-CoA dehydrogenases
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responsible for introducing the first oxidation step and making a double bond
- Usually involved in deficiencies |
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Refsum’s Disease
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- Phytanic acid storage syndrome in alpha oxidation of peroxisomes
- Cannot metabolize phytanic acid - Accumulates in tissues and blood, alpha hydroxylase disorder - Demyleniation of peripheral nerve cells - Avoidance of chlorophyll containing foods, green leafs, meat - Condition improves with improved diet!!!, no phytol in diet!! |
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Zelwegger’s
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- Synthesis of peroxisomes themselves is impaired
- Cannot breakdown VLCFA or LFCA, so accumulation!! - cannot produce pyroxine in peroxisome membranes - also mentioned ALD but very briefly |
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Pathological Ketosis (Uncontrolled diabetes 1)
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NO INSULIN
- Glucose cannot be taken up in the cell - Constant lipolysis and activateion of HSL - Constant flood of NEFAs to the liver, but still no glucose can be taken up! - causes hormone sensitive lipase (in adipocytes) to convert TAG NEFA’s + glycerol - Acetyl CoA highly made >>>OAA available - KB production is thus made!!! o Ketone body production in the liver is increased o Ketonaemia and ketonuria o Kitoacidosis metabolic acidosis o Hyperglycemia |
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Physiological Ketosis (Fasting/Starvation)
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o During 36-48h starvation when blood-glucose levels drop
o O.A.A supply drops as available O.A.A gets shunted to the gluconeogenic pathway Resultant excess in Acetyl-CoA is directed to ketogenesis |
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Deficiency in EFA
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- HIGH levels of MEAD ACID
- Humans do not have desaturases to desatured beyond the delta-9 position - Will try hard to made EFA is not getting them from diet - Will end up trying to do so with mead acid - Levels of mead acid will be high! - Deficiency in linoleic acid (18,2) and a-linolenic acid (18,3) |
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LDLs and Artherosclerosis/Foam Cells
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- LDLs in circulation longer
- Will be modified forming modified LDL - Macrophages will eat LDL and cholesterol will accumulate inside - Will form foam cell and block vessel/damage it - = artherosclerosis!!! |
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Type 1
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LPLase deficiency, low activity of LPLase or ApoCII, high serum TAG
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Type II
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familial hypercholesterolanemia- low LDL receptors, high cholesterol, not getting into cells
- IIa- high LDLs, normal VLDLs |
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- IIb
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high LDL, high VLDL, low HDL
- Good fat can be layed in membranes, BAD FAT impedes LDL receptors=circulating LDLs=PLAQUE! - PRESENT OF xanthomas |
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Type III
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high IDL, high chylomicron remnants
- Apo E related deficiency of uptake of lipoprotein remnants into liver |
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Type IV
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high VLDL
- LPL deficiency - Overproduction of VLDL |
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Type V
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high VLDL high CM
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Tangier’s Disease:
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Tangier’s Disease:
- Rare autosomal disoerder - Low plasma HDL - Cholesterol accumulates in extrahepatic tissues - Engorged macrophages in lymphoid tissues and tonsils - Mutation in ABC1 transporter gene! o Involved in the removal of membrane cholesterol by HDL o Apo-A1 to not aquire cholesterol o Low LDL levels because transfer of CE from HDL to VLDL is not possible |
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Resins
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bile acid sequesterants- block enterohepatic uptake of bile acids
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Thiokinase:
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First step in fatty acid oxidation, ACTIVATION step, forming thioester bond
NEFA + CoA ACYL-CoA Endergonic reaction using ATP Occurs in cytosol Long chain oxidation will occur in mitochondrial matrix!!! After NEFA is exported to other tissues in FASTED STATE, occurs during lipolysis in the CYTOSOL!!! |
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Acyl CoA dehydrogenases
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Participiate in fatty acid oxidation via :
- Oxidation, hydration, oxidation, thiolysis - Will be specific for the type of fatty acid - Will cleave bond during fatty acid oxidation |
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Thiolase
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- Introduced CoA in the last step of fatty acid oxidation
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HSL
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FASTED STATE enzyme,
- in adipose tissue, will be active PHOSPHORYLATED via epinephrine and glucagon - glucagon activates |
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ATP Citrate Lyase
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- Acetyl CoA needed for FAS and must cross the mitrochondrial matrix
- Acetyl Coa will enter the TCA in the mitochondria and make citrate - Citrate will cross the mitochondrial membrane, one there, ATP CITRATE LYASE WILL: o Will convert Citrate to Acetyl CoA and OAA o Acetyl CoA will leave and will be used for FAS o OAA will be further acted upon o OAA will be converted to MALATE |
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MALIC ENZYME
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- Will take malate and convert it to pyruvate
- NADH will be made, that is used in the synthesis of fatty acids, CO2 is further released ACCase |
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ACCase
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- Activate when polymer, multifunctional
- Has biotin carboxylase, transcarboxylase - BCCP CITRATE WILL ACTIVATE THIS! AcetylCoAMalonyl Coa will happen via a :CARBOXYLATION reaction of acetylCoA…NEED BIOTIN!! - First a carboxylation of the BCCP to form CO2-BCCP - Then CO2-BCCP switched with acetyl CoAmalonyl-CoA and BCCP regenerated! - Will be active Dephosphorylated - Glucagon deactivates |
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Regulation of ACCase…
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SHORT TERM:
will be activated by citrate!!!: protomerpolymer Inactivated by LCFA…because why would you want to make fatty acids if already have them as the end product? Inactivated by (Palmytoyl CoA) LONG TERM: Prolonged high carb diets and excess carbs and calories will increase the SYNTHESIS of ACCase. Thus body will be prone to MAKE FAT, FATTY ACID SYNTHESIS constantly taking place!! |
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FAS
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- Malonyl-CoApalmitic acid(16C)
- FAS is a multifunctional enzyme with a flexible arm (ACP) that helps shift substrates between active sites. |
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Desaturases
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- Introduce double bond after palmitic acid is made in FAS…modify fats to make EFAs
- Humans lack desturases beyond the delta 9 position - Cannot make EPA/DHA/arachadonic acid |
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Acyl Transferases
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- Add acyl-CoAs to glycerol 3 phosphate in TAG synthesis
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ACAT
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- In the cytoplasm
- Enzyme in cells that acts on LDL particles - LDL particles will come in via endocytosis - Endosomes will fuse with LDLs and release its contents - Contents include things among cholesterol - ACAT will re-esterify this free cholesterol in order to present it on the cytoplasmic face of the ER! - Will INHIBIT HMG-CoA reductase, sending signal that there is enough cholesterol in the cell already and no more needs to be made - Inhibition of LDL receptor as well |
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essential fatty acids
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linoleic 18:2..will make arachadonic acid, n-6
a-linoleic: 18:3, 9,12,15, will make EPA and DHA...n-3 GOOD KIND |
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B-48
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CM
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B100
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VLDL and LDL, but lower affinity when on LDL
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apoCII
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LPLase recognition
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apo E
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recognition by LDL receptors for remnant uptake
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apo A1
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recognition by LCAT
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lipoprotein (a) and LDL B
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- Assembled in hepatocytes and identicle to LDL particle but with extra apoprotein a with disulphide bond with apo-B100
- Mimics plasminogen and may impair fibrinolysis!! LDL B is modified form of LDL, will easily cross membrane and will impede blood vessels. |
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LCAT
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- LCAT
o In the blood o Will act on the FREE cholesterol in the HDLs and will transfer a PtdCho (lecithin) to the cholesterol and INTERNALIZE it …ENTRAPMENT…will store the cholesterol in the HDL molecule so it can pick up EVEN MORE cholesterol than already has!!! o Requires apo-A1 recognition o Will indirectly reduce level of free cholesterol, regulate compostion of plasma lipoproteins, and cholesterol content of membranes - So after the GOOD FRIENDLY HDL has removed excess cholesterol from extra-heaptic tissues, LCAT will act to internalize this cholesterol via PtdCho addition - This is done so that HDL can pick up EVEN MOREEE cholesterol |
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CETP
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Enzyme involved in reverse cholesterol transport
Important for regulating cholesterol metabolism HDL with all of the cholesterol will give its cholesterol to TAG enriched lipoproteins such as VLDL and LDL. So now HDL has TAG and VLDLs have cholesterol. Hepatic TAG lipase will hydrolyze the TAG-HDL complex in the liver, take up of TAG - Hepatic HDL receptors will take up the HDls and remove them from circulation TAG-HDL particles that have been exchanged are referred to as : HDL 2 particles - May be seen as an atherogenic factor |
