Lipid Metabolism by Dr. de Villa

132
LIPID METABOLISM LIPID METABOLISM Romulo de Villa, MD, PhD, Cert. Biochem. Romulo de Villa, MD, PhD, Cert. Biochem. Molecular & Nutritional Oncologist Molecular & Nutritional Oncologist Professor of Biochemistry & Nutrition Professor of Biochemistry & Nutrition Molecular Biology & Biotechnology Consultant Molecular Biology & Biotechnology Consultant

description

Lipid Metabolism by Dr. de Villa

Transcript of Lipid Metabolism by Dr. de Villa

Page 1: Lipid Metabolism by Dr. de Villa

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

Page 2: Lipid Metabolism by Dr. de Villa

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

Page 3: Lipid Metabolism by Dr. de Villa

Overview (cont.)Overview (cont.)

Phospholipid Metabolism

Glycolipid Metabolism

Metabolism of Prostaglandins and Related compounds

Cholesterol Metabolism

Blood Lipoproteins

Page 4: Lipid Metabolism by Dr. de Villa
Page 5: Lipid Metabolism by Dr. de Villa

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

Page 6: Lipid Metabolism by Dr. de Villa

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

Page 7: Lipid Metabolism by Dr. de Villa

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

Page 8: Lipid Metabolism by Dr. de Villa

Reverse Cholesterol Transport via HDLReverse Cholesterol Transport via HDL

BloodBloodBloodBloodPeripheralPeripheralTissuesTissues

PeripheralPeripheralTissuesTissues

LiverLiverLiverLiver

BileBile

ExcessExcessCholesterolCholesterol

Page 9: Lipid Metabolism by Dr. de Villa

Cholesterol Catabolism into Bile SaltsCholesterol Catabolism into Bile Salts

CholateCholateCholateCholateCholesterolCholesterolCholesterolCholesterol

CholesterolCholesterol77-hydroxylase-hydroxylase

CholesterolCholesterol77-hydroxylase-hydroxylase

HOHOHOHO

OHOH

COO -COO -

OHOH

Page 10: Lipid Metabolism by Dr. de Villa
Page 11: Lipid Metabolism by Dr. de Villa

Bile SaltsBile Salts

Breakdown products of cholesterol

Amphipathic molecules

Function to transport cholesterol in the digestive system

Page 12: Lipid Metabolism by Dr. de Villa

Structure of Biliary and Intestinal MicellesStructure of Biliary and Intestinal Micelles

CholesterolCholesterolCholesterolCholesterol

Bile SaltBile SaltBile SaltBile Salt

PhospholipidPhospholipidPhospholipidPhospholipid

Page 13: Lipid Metabolism by Dr. de Villa

Functions of MicellesFunctions of Micelles

Transport cholesterol from the liver into the intestine via the biliary tree

Participate in fat digestion and absorption

Page 14: Lipid Metabolism by Dr. de Villa

Biliary Lipid SecretionBiliary Lipid Secretion

Sinusoidal Membrane

BloodBloodBloodBlood HepatocyteHepatocyteHepatocyteHepatocyte

Canalicular Membrane

Bile SaltBile SaltBile SaltBile Salt

ABCG5/G8Cholesterol

ABCB4Phospholipid

ABCB11

BileBileBileBile

Page 15: Lipid Metabolism by Dr. de Villa

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

Page 16: Lipid Metabolism by Dr. de Villa

Biliary Lipid TransportBiliary Lipid Transport

DuodenumDuodenumDuodenumDuodenum

JejunumJejunumJejunumJejunum

IleumIleumIleumIleum

ColonColonColonColon

BiliaryBiliaryTransportTransport

and and StorageStorage

BiliaryBiliaryTransportTransport

and and StorageStorage

Liver

Page 17: Lipid Metabolism by Dr. de Villa

Fat DigestionFat Digestion

DuodenumDuodenumDuodenumDuodenum

JejunumJejunumJejunumJejunum

IleumIleumIleumIleum

ColonColonColonColon

BiliaryBiliaryTransportTransport

and and StorageStorage

BiliaryBiliaryTransportTransport

and and StorageStorage

Liver

Page 18: Lipid Metabolism by Dr. de Villa

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

Page 19: Lipid Metabolism by Dr. de Villa

Fat AbsorptionFat Absorption

DuodenumDuodenumDuodenumDuodenum

JejunumJejunumJejunumJejunum

IleumIleumIleumIleum

BiliaryBiliaryTransportTransport

and and StorageStorage

BiliaryBiliaryTransportTransport

and and StorageStorage

ColonColonColonColon

Liver

Page 20: Lipid Metabolism by Dr. de Villa

LymphLymphLymphLymph EnterocyteEnterocyteEnterocyteEnterocyteIntestinalIntestinalLumenLumen

IntestinalIntestinalLumenLumen

Cholesterol AbsorptionCholesterol Absorption

CholesterylEster

ACAT

Cholesterol

IITT

Page 21: Lipid Metabolism by Dr. de Villa

LymphLymphLymphLymph EnterocyteEnterocyteEnterocyteEnterocyte IntestinalIntestinalLumenLumen

IntestinalIntestinalLumenLumen

Triglyceride AbsorptionTriglyceride Absorption

2 Fatty Acid

+Monoglyceride

DGAT

Triglyceride

TTII

Page 22: Lipid Metabolism by Dr. de Villa

LymphLymphLymphLymph EnterocyteEnterocyteEnterocyteEnterocyteIntestinalIntestinalLumenLumen

IntestinalIntestinalLumenLumen

Phospholipid AbsorptionPhospholipid Absorption

Phospholipid

Fatty Acid

+Lysophospholipid

II

Page 23: Lipid Metabolism by Dr. de Villa

LymphLymphLymphLymph EnterocyteEnterocyteEnterocyteEnterocyteIntestinalIntestinalLumenLumen

IntestinalIntestinalLumenLumen

Chylomicron FormationChylomicron Formation

WithapoB48 Cholesteryl

Ester

Triglyceride

Phospholipid

Page 24: Lipid Metabolism by Dr. de Villa

Acetyl-CoA Based MetabolismAcetyl-CoA Based Metabolism

Page 25: Lipid Metabolism by Dr. de Villa

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

Page 26: Lipid Metabolism by Dr. de Villa

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

Page 27: Lipid Metabolism by Dr. de Villa
Page 28: Lipid Metabolism by Dr. de Villa

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

Page 29: Lipid Metabolism by Dr. de Villa
Page 30: Lipid Metabolism by Dr. de Villa
Page 31: Lipid Metabolism by Dr. de Villa

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

Page 32: Lipid Metabolism by Dr. de Villa
Page 33: Lipid Metabolism by Dr. de Villa

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

Page 34: Lipid Metabolism by Dr. de Villa
Page 35: Lipid Metabolism by Dr. de Villa
Page 36: Lipid Metabolism by Dr. de Villa
Page 37: Lipid Metabolism by Dr. de Villa
Page 38: Lipid Metabolism by Dr. de Villa

Synthesis of TriacylglycerolSynthesis of Triacylglycerol

Page 39: Lipid Metabolism by Dr. de Villa

Synthesis of TriacylglycerolSynthesis of Triacylglycerol

Page 40: Lipid Metabolism by Dr. de Villa

Intracellular Fatty acid MetabolismIntracellular Fatty acid Metabolism

Page 41: Lipid Metabolism by Dr. de Villa
Page 42: Lipid Metabolism by Dr. de Villa
Page 43: Lipid Metabolism by Dr. de Villa

Mobilization of Stored Fats: LipolysisMobilization of Stored Fats: Lipolysis

Page 44: Lipid Metabolism by Dr. de Villa
Page 45: Lipid Metabolism by Dr. de Villa
Page 46: Lipid Metabolism by Dr. de Villa

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

Page 47: Lipid Metabolism by Dr. de Villa
Page 48: Lipid Metabolism by Dr. de Villa
Page 49: Lipid Metabolism by Dr. de Villa
Page 50: Lipid Metabolism by Dr. de Villa

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

Page 51: Lipid Metabolism by Dr. de Villa
Page 52: Lipid Metabolism by Dr. de Villa

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

Page 53: Lipid Metabolism by Dr. de Villa
Page 54: Lipid Metabolism by Dr. de Villa

KETOGENESISKETOGENESIS

Page 55: Lipid Metabolism by Dr. de Villa
Page 56: Lipid Metabolism by Dr. de Villa
Page 57: Lipid Metabolism by Dr. de Villa
Page 58: Lipid Metabolism by Dr. de Villa
Page 59: Lipid Metabolism by Dr. de Villa

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

Page 60: Lipid Metabolism by Dr. de Villa

Conversion of Ketone Bodies to Acetyl-CoAConversion of Ketone Bodies to Acetyl-CoA

Page 61: Lipid Metabolism by Dr. de Villa
Page 62: Lipid Metabolism by Dr. de Villa
Page 63: Lipid Metabolism by Dr. de Villa

Cholesterol SynthesisCholesterol Synthesis

Page 64: Lipid Metabolism by Dr. de Villa
Page 65: Lipid Metabolism by Dr. de Villa
Page 66: Lipid Metabolism by Dr. de Villa
Page 67: Lipid Metabolism by Dr. de Villa
Page 68: Lipid Metabolism by Dr. de Villa
Page 69: Lipid Metabolism by Dr. de Villa

Cholesterol BalanceCholesterol Balance

Page 70: Lipid Metabolism by Dr. de Villa

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

Page 71: Lipid Metabolism by Dr. de Villa

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

Page 72: Lipid Metabolism by Dr. de Villa

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

Page 73: Lipid Metabolism by Dr. de Villa

Inhibitors of Cholesterol Synthesis Inhibitors of Cholesterol Synthesis

and Absorptionand Absorption

Page 74: Lipid Metabolism by Dr. de Villa

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

Page 75: Lipid Metabolism by Dr. de Villa

LDLLDLReceptorReceptor

LDLLDLReceptorReceptor

StatinsStatins

Acetate

LDLLDLLDLLDL

HMG-CoAReductase

Cholesterol

Page 76: Lipid Metabolism by Dr. de Villa

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

Page 77: Lipid Metabolism by Dr. de Villa

Plant Sterols and StanolsPlant Sterols and Stanols

Sterol/StanolSterol/StanolSterol/StanolSterol/StanolDietaryDietaryCholesterolCholesterol

DietaryDietaryCholesterolCholesterol

Page 78: Lipid Metabolism by Dr. de Villa

LymphLymphLymphLymph EnterocyteEnterocyteEnterocyteEnterocyte IntestinalIntestinalLumenLumen

IntestinalIntestinalLumenLumen

Plant Sterols and StanolsPlant Sterols and Stanols

Cholesterol

CholesterylEster ABCG5/G8

ACAT NPC1L1

Page 79: Lipid Metabolism by Dr. de Villa

LymphLymphLymphLymph EnterocyteEnterocyteEnterocyteEnterocyte IntestinalIntestinalLumenLumen

IntestinalIntestinalLumenLumen

EzetimibeEzetimibe

Cholesterol

NPC1L1

CholesterylEster ABCG5/G8

ACAT

Ezetimibe

XX

Page 80: Lipid Metabolism by Dr. de Villa

LymphLymphLymphLymph EnterocyteEnterocyteEnterocyteEnterocyte IntestinalIntestinalLumenLumen

IntestinalIntestinalLumenLumen

Cholesterol Absorption InhibitorsCholesterol Absorption Inhibitors

CholesterylEster

CMapoB48

Triglyceride

Page 81: Lipid Metabolism by Dr. de Villa

Cholesterol Absorption InhibitorsCholesterol Absorption Inhibitors

DuodenumDuodenumDuodenumDuodenum

JejunumJejunumJejunumJejunum

IleumIleumIleumIleum

CMapoB48

Liver

CM RemnantapoB48

VLDLapoB100

EzetimibeXX

LDLapoB100

ColonColonColonColon

Page 82: Lipid Metabolism by Dr. de Villa

Dual InhibitionDual Inhibition

Page 83: Lipid Metabolism by Dr. de Villa

Assembly and Secretion of VLDLAssembly and Secretion of VLDL

Presence of TriglyceridesPresence of Triglycerides

ApoB

MTPMTP

Cholesteryl Esters

Cholesterol

Dietary/Biliary Synthesis

Page 84: Lipid Metabolism by Dr. de Villa

Effect of Cholesterol Absorption InhibitorEffect of Cholesterol Absorption Inhibitor

Presence of TriglyceridesPresence of Triglycerides

ApoB

Cholesterol

Dietary/Biliary Synthesis

EzetimibeXX

MTPMTP

Cholesteryl Esters

Page 85: Lipid Metabolism by Dr. de Villa

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

Page 86: Lipid Metabolism by Dr. de Villa

Dual InhibitionDual Inhibition

DuodenumDuodenumDuodenumDuodenum

JejunumJejunumJejunumJejunum

IleumIleumIleumIleum

CMapoB48

Liver

CM RemnantapoB48

VLDLapoB100

EzetimibeXX

LDLapoB100

XXStatinStatin

ColonColonColonColon

Page 87: Lipid Metabolism by Dr. de Villa

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

Page 88: Lipid Metabolism by Dr. de Villa

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 !

Page 89: Lipid Metabolism by Dr. de Villa

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!

Page 90: Lipid Metabolism by Dr. de Villa

High LDL-Cholesterol is a Major Culprit for Cardiovascular RiskHigh LDL-Cholesterol is a Major Culprit for Cardiovascular Risk

Page 91: Lipid Metabolism by Dr. de Villa

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

Page 92: Lipid Metabolism by Dr. de Villa

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

Page 93: Lipid Metabolism by Dr. de Villa

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

Page 94: Lipid Metabolism by Dr. de Villa

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)

Page 95: Lipid Metabolism by Dr. de Villa

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

Page 96: Lipid Metabolism by Dr. de Villa

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

Page 97: Lipid Metabolism by Dr. de Villa

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

Page 98: Lipid Metabolism by Dr. de Villa

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

Page 99: Lipid Metabolism by Dr. de Villa

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

Page 100: Lipid Metabolism by Dr. de Villa

Metabolism of Metabolism of Amphipathic LipidsAmphipathic Lipids

Page 101: Lipid Metabolism by Dr. de Villa

Phospholipid SynthesisPhospholipid Synthesis

Page 102: Lipid Metabolism by Dr. de Villa

Conversion of Phosphatidylethanolamine to Conversion of Phosphatidylethanolamine to phosphatidylcholinephosphatidylcholine

Page 103: Lipid Metabolism by Dr. de Villa
Page 104: Lipid Metabolism by Dr. de Villa
Page 105: Lipid Metabolism by Dr. de Villa
Page 106: Lipid Metabolism by Dr. de Villa
Page 107: Lipid Metabolism by Dr. de Villa
Page 108: Lipid Metabolism by Dr. de Villa
Page 109: Lipid Metabolism by Dr. de Villa

Metabolism of Metabolism of Unsaturated Fatty AcidsUnsaturated Fatty Acids

Page 110: Lipid Metabolism by Dr. de Villa
Page 111: Lipid Metabolism by Dr. de Villa

Desaturation of Stearoyl-CoADesaturation of Stearoyl-CoA

Page 112: Lipid Metabolism by Dr. de Villa
Page 113: Lipid Metabolism by Dr. de Villa
Page 114: Lipid Metabolism by Dr. de Villa
Page 115: Lipid Metabolism by Dr. de Villa
Page 116: Lipid Metabolism by Dr. de Villa
Page 117: Lipid Metabolism by Dr. de Villa
Page 118: Lipid Metabolism by Dr. de Villa

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

Page 119: Lipid Metabolism by Dr. de Villa

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

Page 120: Lipid Metabolism by Dr. de Villa

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

Page 121: Lipid Metabolism by Dr. de Villa

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

Page 122: Lipid Metabolism by Dr. de Villa

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

Page 123: Lipid Metabolism by Dr. de Villa

LipoProteinsLipoProteins

Page 124: Lipid Metabolism by Dr. de Villa
Page 125: Lipid Metabolism by Dr. de Villa
Page 126: Lipid Metabolism by Dr. de Villa
Page 127: Lipid Metabolism by Dr. de Villa
Page 128: Lipid Metabolism by Dr. de Villa
Page 129: Lipid Metabolism by Dr. de Villa
Page 130: Lipid Metabolism by Dr. de Villa
Page 131: Lipid Metabolism by Dr. de Villa
Page 132: Lipid Metabolism by Dr. de Villa