Lipid Metabolism by Dr. de Villa
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LIPID METABOLISMLIPID METABOLISM
Romulo de Villa, MD, PhD, Cert. Biochem.Romulo de Villa, MD, PhD, Cert. Biochem.
Molecular & Nutritional OncologistMolecular & Nutritional OncologistProfessor of Biochemistry & NutritionProfessor of Biochemistry & NutritionMolecular Biology & Biotechnology ConsultantMolecular Biology & Biotechnology Consultant
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OverviewOverview
Digestive lipid metabolism
De Novo Synthesis of Fatty acid
Synthesis of Triacylglycerols
Mobilization of Stored Fats and Oxidation of Fatty acids
Synthesis of Ketone bodies
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Overview (cont.)Overview (cont.)
Phospholipid Metabolism
Glycolipid Metabolism
Metabolism of Prostaglandins and Related compounds
Cholesterol Metabolism
Blood Lipoproteins
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Emulsification of Dietary lipids in the small Emulsification of Dietary lipids in the small
intestinesintestines
- emulsification inc. the surface area - emulsification inc. the surface area
lipase activity lipase activity
- detergent property of bile salt and - detergent property of bile salt and
peristalsis peristalsis> Pancreatic activity> Pancreatic activity
A. Hormonal Control of Lipid DigestionA. Hormonal Control of Lipid Digestion
1. CCK/pancreozymin – (+)GB contraction 1. CCK/pancreozymin – (+)GB contraction
and release of bile; release of pancreatic and release of bile; release of pancreatic
enzymes; dec. gastric motilityenzymes; dec. gastric motility
2.2. Secretin - (+) bicarbonate secretionSecretin - (+) bicarbonate secretion
Digestive Lipid MetabolismDigestive Lipid Metabolism
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1. Triacyglycerol hydrolysis1. Triacyglycerol hydrolysis
- TAG are acted upon by pancreatic lipase - TAG are acted upon by pancreatic lipase
and removes FA at carbon 1 and 3and removes FA at carbon 1 and 3
- products = 2-monoacylglycerol + FA- products = 2-monoacylglycerol + FA
2. Cholesteryl ester degradation2. Cholesteryl ester degradation
- Cholesterol esterase- Cholesterol esterase
- Products: Cholesterol + FA- Products: Cholesterol + FA
3. Phospholipids degradation3. Phospholipids degradation
- phospholipase A- phospholipase A22
- products: lysophospholipid + FA- products: lysophospholipid + FA
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Absorption of Lipids by intestinal mucosal cellsAbsorption of Lipids by intestinal mucosal cells
- FFA, free cholesterol, 2-monoacylglycerol and - FFA, free cholesterol, 2-monoacylglycerol and
lysophospholipid together with bile salts from mixed lysophospholipid together with bile salts from mixed
micelles which is absorbed at the brush border micelles which is absorbed at the brush border
membrane of SImembrane of SI
- short and medium chain FA are directly absorbed- short and medium chain FA are directly absorbed
> Resynthesis of TAG, CE and PL> Resynthesis of TAG, CE and PL
2-monoacylglycerol + fatty acyl-CoA = TAG 2-monoacylglycerol + fatty acyl-CoA = TAG
Cholesterol + FA = CECholesterol + FA = CE
Lysophospholipid + FA = PhospholipidLysophospholipid + FA = Phospholipid
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Reverse Cholesterol Transport via HDLReverse Cholesterol Transport via HDL
BloodBloodBloodBloodPeripheralPeripheralTissuesTissues
PeripheralPeripheralTissuesTissues
LiverLiverLiverLiver
BileBile
ExcessExcessCholesterolCholesterol
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Cholesterol Catabolism into Bile SaltsCholesterol Catabolism into Bile Salts
CholateCholateCholateCholateCholesterolCholesterolCholesterolCholesterol
CholesterolCholesterol77-hydroxylase-hydroxylase
CholesterolCholesterol77-hydroxylase-hydroxylase
HOHOHOHO
OHOH
COO -COO -
OHOH
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Bile SaltsBile Salts
Breakdown products of cholesterol
Amphipathic molecules
Function to transport cholesterol in the digestive system
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Structure of Biliary and Intestinal MicellesStructure of Biliary and Intestinal Micelles
CholesterolCholesterolCholesterolCholesterol
Bile SaltBile SaltBile SaltBile Salt
PhospholipidPhospholipidPhospholipidPhospholipid
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Functions of MicellesFunctions of Micelles
Transport cholesterol from the liver into the intestine via the biliary tree
Participate in fat digestion and absorption
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Biliary Lipid SecretionBiliary Lipid Secretion
Sinusoidal Membrane
BloodBloodBloodBlood HepatocyteHepatocyteHepatocyteHepatocyte
Canalicular Membrane
Bile SaltBile SaltBile SaltBile Salt
ABCG5/G8Cholesterol
ABCB4Phospholipid
ABCB11
BileBileBileBile
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Biliary LipidsBiliary Lipids
Daily Secretion (g)Daily Secretion (g)Daily Secretion (g)Daily Secretion (g)Lipid ClassLipid ClassLipid ClassLipid Class
Bile salts
Phospholipids
Cholesterol
24
11
2
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Biliary Lipid TransportBiliary Lipid Transport
DuodenumDuodenumDuodenumDuodenum
JejunumJejunumJejunumJejunum
IleumIleumIleumIleum
ColonColonColonColon
BiliaryBiliaryTransportTransport
and and StorageStorage
BiliaryBiliaryTransportTransport
and and StorageStorage
Liver
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Fat DigestionFat Digestion
DuodenumDuodenumDuodenumDuodenum
JejunumJejunumJejunumJejunum
IleumIleumIleumIleum
ColonColonColonColon
BiliaryBiliaryTransportTransport
and and StorageStorage
BiliaryBiliaryTransportTransport
and and StorageStorage
Liver
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F a t D i g e s t i o nF a t D i g e s t i o n
I III
III
III II
IIII
Fatty Acids +Fatty Acids +LysophospholipidLysophospholipid
Fatty Acids +Fatty Acids +LysophospholipidLysophospholipid
PhospholipidsPhospholipidsPhospholipidsPhospholipids
III
TriglyceridesTriglyceridesTriglyceridesTriglycerides
Fatty Acids +Fatty Acids +MonoglyceridesMonoglyceridesFatty Acids +Fatty Acids +
MonoglyceridesMonoglyceridesI
I
IIIIIIII
I IIIIII
III
DietaryDietaryCholesterolCholesterol
DietaryDietaryCholesterolCholesterol
I I I
III
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Fat AbsorptionFat Absorption
DuodenumDuodenumDuodenumDuodenum
JejunumJejunumJejunumJejunum
IleumIleumIleumIleum
BiliaryBiliaryTransportTransport
and and StorageStorage
BiliaryBiliaryTransportTransport
and and StorageStorage
ColonColonColonColon
Liver
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LymphLymphLymphLymph EnterocyteEnterocyteEnterocyteEnterocyteIntestinalIntestinalLumenLumen
IntestinalIntestinalLumenLumen
Cholesterol AbsorptionCholesterol Absorption
CholesterylEster
ACAT
Cholesterol
IITT
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LymphLymphLymphLymph EnterocyteEnterocyteEnterocyteEnterocyte IntestinalIntestinalLumenLumen
IntestinalIntestinalLumenLumen
Triglyceride AbsorptionTriglyceride Absorption
2 Fatty Acid
+Monoglyceride
DGAT
Triglyceride
TTII
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LymphLymphLymphLymph EnterocyteEnterocyteEnterocyteEnterocyteIntestinalIntestinalLumenLumen
IntestinalIntestinalLumenLumen
Phospholipid AbsorptionPhospholipid Absorption
Phospholipid
Fatty Acid
+Lysophospholipid
II
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LymphLymphLymphLymph EnterocyteEnterocyteEnterocyteEnterocyteIntestinalIntestinalLumenLumen
IntestinalIntestinalLumenLumen
Chylomicron FormationChylomicron Formation
WithapoB48 Cholesteryl
Ester
Triglyceride
Phospholipid
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Acetyl-CoA Based MetabolismAcetyl-CoA Based Metabolism
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De Novo Synthesis of Fatty AcidsDe Novo Synthesis of Fatty Acids
Production of Acetyl CoA
Carboxylation of Acetyl CoA
Fatty acid synthase: a multienzyme complexAcetylCoA-ACP transacylaseMalonylCoA-ACP transacylaseß-ketoacyl-ACO synthasePalmitoyl thioesterase
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De Novo Synthesis of Fatty AcidsDe Novo Synthesis of Fatty Acids
Production of Acetyl CoA
Translocation of mitochondrial citrate to cytosol
Conversion of citrate to acetyl CoA + oxaloacetate by citrate lyase
Requirement: Inc. ATP and Citrate
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De Novo Synthesis of Fatty AcidsDe Novo Synthesis of Fatty Acids Carboxylation of
acetyl CoA to malonyl CoA
Regulators of acetylCoA carboxylase Activators:
insulin,Inc. CHO intake, fat-free diet
Inhibitors: malonyl CoA, palmitoyl CoA,epinephrine,
fasting, high fat diet
Carboxylation of AcetylCoA to malonylCoA by AcetylCoA carboxylase
Rate limiting step in fatty acid synthesis
Coenzyme: Biotin
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De Novo Synthesis of Fatty AcidsDe Novo Synthesis of Fatty Acids Fatty acid synthase: a
multienzyme complex Substrate: AcetylCoA
and MalonylCoA End Product: Palmitic
acid Site: Cytosol Priming Molecule:
Acetyl CoA Rate-limiting enzyme:
Acetyl CoA carboxylase Primary enzyme of
synthesis: Fatty acid synthase
Carbons 15 and 16 of palmitic acid from priming acetyl CoA
Carbons 1-14 of palmitic acid are derived from 7 malonyl CoA ( 2 carbons from malonyl CoA are added 7 times to the priming acetylCoA molecule
NADPH + H+ are from HMP-Shunt
1 AcetylCoA + 7 malonylCoA + 14 NADPH+ 14 H
Palmitic acid + 7 CO2 + 6H2O+ Co-A-SH +14 NADP
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De Novo Fatty Acid SynthesisDe Novo Fatty Acid Synthesis
1. AcetylCoA + ACP-SH AcetylCoA-ACP-transacylase Acetyl-S-ACP + CoA
2. Acetyl-S-ACP + Enzyme SH Acetyl-S-enzyme + ACP-SH
3. MalonylCoA + ACP-SH Malonyl-ACP Transacylase Malonyl-S-ACP + CoA
4. Malonyl-S-ACP + Acetyl-S-enzyme ß-ketoacyl-ACO synthase Acetoacetyl-S-
ACP + CO2
5,6,7 Three steps: 2 reductions + dehydrogenation step: converts ketoacyl group to saturated acyl group
The cycle of reactions is repeated 7X, each time incorporating a two-carbon unit from malonyl CoA into the growing fatty acid chain
Palmitoyl-S-ACP + H2O Palmitoyl thioesterase Palmitate + ACP-SH
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Synthesis of TriacylglycerolSynthesis of Triacylglycerol
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Synthesis of TriacylglycerolSynthesis of Triacylglycerol
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Intracellular Fatty acid MetabolismIntracellular Fatty acid Metabolism
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Mobilization of Stored Fats: LipolysisMobilization of Stored Fats: Lipolysis
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Beta-Oxidation of Fatty AcidsBeta-Oxidation of Fatty Acids
major pathway for catabolism of saturated FA
2-carbon fragments are successively removed from the carboxyl end of the fatty acylCoA, producing acetylCoA
Consists of four reactions: shortening of FA by 2 carbons Oxidation: produces FADH2
Hydration: produces NADH Thiolytic cleavage: produces 2 acetylCoA
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ENERGY YIELD FROM ß-OXIDATIONENERGY YIELD FROM ß-OXIDATION
From PalmitoylCoA ATP Yield
7NADH x 3 ATP by ETC oxidation 21
7 FADH2 x 2 ATP by ETC oxidation 14
8 Acetyl CoA x 12 ATP via Krebs CAC 96
Total (Gross) 131 ATP
Less 2 ATP
NET 129 ATP
From one molecule of palmitoylCoA
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Ketone Bodies: Alternative Fuel for CellsKetone Bodies: Alternative Fuel for Cells
Ketone Bodies: acetoacetic acid, BHBA,acetone
Produced in the liver when the amount of acetylCoA exceeds the oxidative capacity of the liver
Extrahepatic tissues that can utilize Ketone bodies Skeletal muscles Cardiac muscles Renal cortex Brain
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KETOGENESISKETOGENESIS
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Utilization of Ketone BodiesUtilization of Ketone Bodies
Liver produces Ketone bodies
Liver cannot use acetoacetate as fuel ( lacks thiophorase : enzyme for the conversion of acetoacetate to acetoacetylCoA
AcetoacetylCoA is converted to 2 acetylCoA which are oxidized by the TCA
Increased Ketogenesis Conditions
Starvation Severe DM Rapid mobilization
of fat Result to
ketonemia ketoacidosis
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Conversion of Ketone Bodies to Acetyl-CoAConversion of Ketone Bodies to Acetyl-CoA
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Cholesterol SynthesisCholesterol Synthesis
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Cholesterol BalanceCholesterol Balance
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DuodenumDuodenumDuodenumDuodenum
JejunumJejunumJejunumJejunum
IleumIleumIleumIleum
ColonColonColonColon
Portal Venous Return (>95% of Biliary
Secretion)
Portal Venous Return (>95% of Biliary
Secretion) FecalFecalexcretionexcretion(0.4 g/d)(0.4 g/d)
FecalFecalexcretionexcretion(0.4 g/d)(0.4 g/d)
BiliaryBiliaryTransportTransport
and and StorageStorage
BiliaryBiliaryTransportTransport
and and StorageStorage
LiverSynthesisSynthesis
0.4 g/d0.4 g/d
SecretionSecretion24 g/d24 g/d
Enterohepatic Circulation of Bile SaltsEnterohepatic Circulation of Bile Salts
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DuodenumDuodenumDuodenumDuodenum
JejunumJejunumJejunumJejunum
IleumIleumIleumIleum
ColonColonColonColon
BiliaryBiliaryTransportTransport
and and StorageStorage
BiliaryBiliaryTransportTransport
and and StorageStorage
FecalFecalexcretionexcretion(1.2 g/d)(1.2 g/d)
FecalFecalexcretionexcretion(1.2 g/d)(1.2 g/d)
DietaryDietaryCholesterolCholesterol
(0.4 g/d)(0.4 g/d)
DietaryDietaryCholesterolCholesterol
(0.4 g/d)(0.4 g/d)
AbsorptionAbsorption~50%~50%
AbsorptionAbsorption~50%~50%
CMapoB48
LiverBiliary Biliary
Cholesterol Cholesterol (2 g/d)(2 g/d)
Biliary and Dietary CholesterolBiliary and Dietary Cholesterol
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Cholesterol BalanceCholesterol Balance
DuodenumDuodenumDuodenumDuodenum
JejunumJejunumJejunumJejunum
IleumIleumIleumIleum
ColonColonColonColon
BiliaryBiliaryTransportTransport
and and StorageStorage
BiliaryBiliaryTransportTransport
and and StorageStorage
CholesterolCholesterol
CholesterolCholesterol(1.2 g/d)(1.2 g/d)
++Bile SaltsBile Salts(0.4 g/d)(0.4 g/d)
CholesterolCholesterol(1.2 g/d)(1.2 g/d)
++Bile SaltsBile Salts(0.4 g/d)(0.4 g/d)
DietaryDietaryCholesterolCholesterol
(0.4 g/d)(0.4 g/d)
DietaryDietaryCholesterolCholesterol
(0.4 g/d)(0.4 g/d)
LossLoss(1.6 g/d)(1.6 g/d)
Bile saltsBile saltsLossLoss
(1.6 g/d)(1.6 g/d)——
DietaryDietaryCholesterolCholesterol
(0.4 g/d)(0.4 g/d)
LossLoss(1.6 g/d)(1.6 g/d)
——DietaryDietary
CholesterolCholesterol(0.4 g/d)(0.4 g/d)
SynthesisSynthesis(1.2 g/d)(1.2 g/d)
Liver
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Inhibitors of Cholesterol Synthesis Inhibitors of Cholesterol Synthesis
and Absorptionand Absorption
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Inhibitors of Cholesterol Synthesis: StatinsInhibitors of Cholesterol Synthesis: Statins
Inhibit synthesis of cholesterol by cells
Lower LDL cholesterol
Mechanism: Mechanism: Promote LDL ClearancePromote LDL Clearance
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LDLLDLReceptorReceptor
LDLLDLReceptorReceptor
StatinsStatins
Acetate
LDLLDLLDLLDL
HMG-CoAReductase
Cholesterol
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Cholesterol Absorption InhibitorsCholesterol Absorption Inhibitors
Inhibit absorption of dietary cholesterol
Inhibit reabsorption of biliary cholesterol
Lower LDL cholesterol
Mechanism: Mechanism: Inhibit LDL FormationInhibit LDL Formation
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Plant Sterols and StanolsPlant Sterols and Stanols
Sterol/StanolSterol/StanolSterol/StanolSterol/StanolDietaryDietaryCholesterolCholesterol
DietaryDietaryCholesterolCholesterol
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LymphLymphLymphLymph EnterocyteEnterocyteEnterocyteEnterocyte IntestinalIntestinalLumenLumen
IntestinalIntestinalLumenLumen
Plant Sterols and StanolsPlant Sterols and Stanols
Cholesterol
CholesterylEster ABCG5/G8
ACAT NPC1L1
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LymphLymphLymphLymph EnterocyteEnterocyteEnterocyteEnterocyte IntestinalIntestinalLumenLumen
IntestinalIntestinalLumenLumen
EzetimibeEzetimibe
Cholesterol
NPC1L1
CholesterylEster ABCG5/G8
ACAT
Ezetimibe
XX
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LymphLymphLymphLymph EnterocyteEnterocyteEnterocyteEnterocyte IntestinalIntestinalLumenLumen
IntestinalIntestinalLumenLumen
Cholesterol Absorption InhibitorsCholesterol Absorption Inhibitors
CholesterylEster
CMapoB48
Triglyceride
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Cholesterol Absorption InhibitorsCholesterol Absorption Inhibitors
DuodenumDuodenumDuodenumDuodenum
JejunumJejunumJejunumJejunum
IleumIleumIleumIleum
CMapoB48
Liver
CM RemnantapoB48
VLDLapoB100
EzetimibeXX
LDLapoB100
ColonColonColonColon
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Dual InhibitionDual Inhibition
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Assembly and Secretion of VLDLAssembly and Secretion of VLDL
Presence of TriglyceridesPresence of Triglycerides
ApoB
MTPMTP
Cholesteryl Esters
Cholesterol
Dietary/Biliary Synthesis
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Effect of Cholesterol Absorption InhibitorEffect of Cholesterol Absorption Inhibitor
Presence of TriglyceridesPresence of Triglycerides
ApoB
Cholesterol
Dietary/Biliary Synthesis
EzetimibeXX
MTPMTP
Cholesteryl Esters
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Adding a Statin Blocks Compensatory Increase in Adding a Statin Blocks Compensatory Increase in SynthesisSynthesis
Presence of TriglyceridesPresence of Triglycerides
ApoB
Cholesterol
Dietary/Biliary Synthesis
EzetimibeXX XX Statin
MTPMTP
Cholesteryl Esters
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Dual InhibitionDual Inhibition
DuodenumDuodenumDuodenumDuodenum
JejunumJejunumJejunumJejunum
IleumIleumIleumIleum
CMapoB48
Liver
CM RemnantapoB48
VLDLapoB100
EzetimibeXX
LDLapoB100
XXStatinStatin
ColonColonColonColon
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ConclusionsConclusions
Cholesterol balance is regulated by both synthesis and absorption
Inhibition of cholesterol absorption may be compensated by increases in synthesis
Optimal LDL lowering may best be achieved by inhibiting both pathways
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The very first The very first symptom for 1/3 of symptom for 1/3 of
all the heart all the heart attacks that occur attacks that occur
each and every day each and every day is . . .is . . .
INSTANTINSTANTDEATH !DEATH !
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Stress, Stress, Smoking, Smoking, Lack of exercise, Poor Lack of exercise, Poor nutrition nutrition and of course, and of course, Genetics Genetics all contribute to all contribute to HEART DISEASE!HEART DISEASE! But But the real culprit is,the real culprit is,
HIGHHIGHCHOLESTEROL!CHOLESTEROL!
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High LDL-Cholesterol is a Major Culprit for Cardiovascular RiskHigh LDL-Cholesterol is a Major Culprit for Cardiovascular Risk
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Cholesterol is everywhere Cholesterol is everywhere in the Body ?in the Body ?
Inside Cells Hepatic Tissue Extrahepatic Tissue
Outside Cells Connective Tissue (Blood)
Within Cell Membranes
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Why is Cholesterol all over the body ?Why is Cholesterol all over the body ?
Cells synthesize cholesterol
Cholesterol is needed Cholesterol esterification for transfer from one
lipoprotein (HDL) to other lipoproteins (VLDL, IDL & LDL) Bile synthesis for emulsification of dietary fat Steroid hormone synthesis
Androgens Estrogens Corticosteroid Glucocorticoids
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Cholesterol Has No MoralityCholesterol Has No Morality
There is no difference in the molecular structure of good and bad cholesterol
The type of apoprotein holding the cholesterol will determine the morality of cholesterol
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HDL Cholesterol is Good CholesterolCholesterol is brought to the liver when HDL
binds to the liverCholesterol is transferred to other lipoprotins
(VLDL, LDL, IDL)Lecithin/Cholesterol AcylTransferase
(LCAT) converts cholesterol to cholesteryl esters
Cholesterol esters transferred to other lipoprotein (VLDL, LDL, IDL)
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LDL Cholesterol is Bad Cholesterol only when cholesterol becomes deposited on the blood vessel
wall as part of repair of disrupted endothelial lining due
to endothelial dysfunction if the carrier LDL is oxidized
LDL cholesterol is not all that bad Cholesterol is brought to tissues for further
metabolism Tissues need cholesterol
for hormone synthesis to modulate membrane fluidity
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Framingham StudyFramingham Study
70% of men with Coronary Heart Disease (CHD) had <44 mg/dL HDL-cholesterol 1.5 % risk if HDL-c > 35 mg/dL 7.2 % risk if t-chol/HDL-c > 5
HDL-c & Trigly are low 11.5 % risk if t-chol/HDL-c > 5
HDL-c < 35 mg/dL Trigly > 200 mg/dL
The higher the HDL-c the lower the rate of CHD
Normal Ratio of t-cholesterol / HDL-c = < 5
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Low Lipid Levels in FilipinosLow Lipid Levels in Filipinos
Triglyceride 116 mg/dL
Cholesterol 159 mg/dL
HDL-c 30 mg/dL T-Chole/HDLc Ratio > 5 HDLc < 35
LDL-c 107 mg/dL
Evaluation: The low HDL-c is a high risk for Filipinos
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Roles of HDL ApoproteinsRoles of HDL Apoproteins
Brings cholesterol from peripheral tissues (including arteries) to the liver Removing cholesterol from arterial wall Inhibiting growth of new plaques
Enhances stability of plaques and inhibits plaque rupture
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Provides cholesteryl esters to LDL
Protects LDL-cholesterol from oxidation by acting as a good anti-oxidant when HDL
attaches to LDL
Reduce expression of adhesion molecules on the vascular endothelium Reduced adhesion of leukocytes (early phase of
atherogenesis), prevent formation of new plaques, maintain integrity vascular endothelium
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Metabolism of Metabolism of Amphipathic LipidsAmphipathic Lipids
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Phospholipid SynthesisPhospholipid Synthesis
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Conversion of Phosphatidylethanolamine to Conversion of Phosphatidylethanolamine to phosphatidylcholinephosphatidylcholine
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Metabolism of Metabolism of Unsaturated Fatty AcidsUnsaturated Fatty Acids
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Desaturation of Stearoyl-CoADesaturation of Stearoyl-CoA
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Why is DM a risk factor for MI?Why is DM a risk factor for MI?
Most type 2 diabetics die of heart attack.
• Peroxisome-Proliferator activated receptor (PPAR) links Type 2 diabetes mellitus with heart attack
PPAR activity
Free fatty acids
Free fatty acid uptake
Insulin resistance
Complement 3
Atherosclerosis is an inflammation-based process
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Why is DM a risk factor for MI?Why is DM a risk factor for MI?
Most type 2 diabetics die of heart attack.
• Peroxisome-Proliferator activated receptor (PPAR) links Type 2 diabetes mellitus with heart attack
PPAR activity
regulation of gene expression
Apoproteins of lipoproteinsEnzymes of CHO & lipid metabolism
Free fatty acids
Free fatty acid uptake
Insulin resistance
Complement 3
Atherosclerosis is an inflammation-based process
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PPAR gamma plays a critical role in the regulation of cholesterol homeostasis by controlling the expression of a network of genes that
mediate cholesterol efflux from cells
Responsible for degeneration of ABC-I, cholesterol transporter from the cells to HDL-3
transport in plasma Inhibits production of apolipoprotein & C3 which destroys Apo-B (ligand that binds LDL to its
receptors) and LDL accumulates Apo-B ligand function can also be destroyed y
oxidation of the protein
Functions of PPAR
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Nullifies inflammatory action of nuclear factor kappa B (NFkB), a nuclear receptor normally at rest in the cell but may be activated during atherosclerosis
Produce cellular or macrophage apoptosis which dampens inflammatory changes occurring in the vessel wall
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Why is DM a risk factor for MI?Why is DM a risk factor for MI?
Most type 2 diabetics die of heart attack.
• Peroxisome-Proliferator activated receptor (PPAR) links Type 2 diabetes mellitus with heart attack
PPAR activity
regulation of gene expression
Apoproteins of lipoproteinsEnzymes of CHO & lipid metabolism
glitazone, fibrates, statins PUFA (omega-3 ?)
Free fatty acids
Free fatty acid uptake
Insulin resistance
Complement 3
Atherosclerosis is an inflammation-based process
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LipoProteinsLipoProteins
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