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

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

Overview (cont.)Overview (cont.)

Phospholipid Metabolism

Glycolipid Metabolism

Metabolism of Prostaglandins and Related compounds

Cholesterol Metabolism

Blood Lipoproteins

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

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

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

Reverse Cholesterol Transport via HDLReverse Cholesterol Transport via HDL

BloodBloodBloodBloodPeripheralPeripheralTissuesTissues

PeripheralPeripheralTissuesTissues

LiverLiverLiverLiver

BileBile

ExcessExcessCholesterolCholesterol

Cholesterol Catabolism into Bile SaltsCholesterol Catabolism into Bile Salts

CholateCholateCholateCholateCholesterolCholesterolCholesterolCholesterol

CholesterolCholesterol77-hydroxylase-hydroxylase

HOHOHOHO

COO -COO -

Bile SaltsBile Salts

Breakdown products of cholesterol

Amphipathic molecules

Function to transport cholesterol in the digestive system

Structure of Biliary and Intestinal MicellesStructure of Biliary and Intestinal Micelles

CholesterolCholesterolCholesterolCholesterol

Bile SaltBile SaltBile SaltBile Salt

PhospholipidPhospholipidPhospholipidPhospholipid

Functions of MicellesFunctions of Micelles

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

Participate in fat digestion and absorption

Biliary Lipid SecretionBiliary Lipid Secretion

Sinusoidal Membrane

BloodBloodBloodBlood HepatocyteHepatocyteHepatocyteHepatocyte

Canalicular Membrane

Bile SaltBile SaltBile SaltBile Salt

ABCG5/G8Cholesterol

ABCB4Phospholipid

ABCB11

BileBileBileBile

Biliary LipidsBiliary Lipids

Daily Secretion (g)Daily Secretion (g)Daily Secretion (g)Daily Secretion (g)Lipid ClassLipid ClassLipid ClassLipid Class

Bile salts

Phospholipids

Cholesterol

Biliary Lipid TransportBiliary Lipid Transport

DuodenumDuodenumDuodenumDuodenum

JejunumJejunumJejunumJejunum

IleumIleumIleumIleum

ColonColonColonColon

BiliaryBiliaryTransportTransport

and and StorageStorage

Fat DigestionFat Digestion

F a t D i g e s t i o nF a t D i g e s t i o n

III II

Fatty Acids +Fatty Acids +LysophospholipidLysophospholipid

PhospholipidsPhospholipidsPhospholipidsPhospholipids

TriglyceridesTriglyceridesTriglyceridesTriglycerides

Fatty Acids +Fatty Acids +MonoglyceridesMonoglyceridesFatty Acids +Fatty Acids +

MonoglyceridesMonoglyceridesI

IIIIIIII

I IIIIII

DietaryDietaryCholesterolCholesterol

Fat AbsorptionFat Absorption

LymphLymphLymphLymph EnterocyteEnterocyteEnterocyteEnterocyteIntestinalIntestinalLumenLumen

IntestinalIntestinalLumenLumen

Cholesterol AbsorptionCholesterol Absorption

CholesterylEster

Cholesterol

LymphLymphLymphLymph EnterocyteEnterocyteEnterocyteEnterocyte IntestinalIntestinalLumenLumen

Triglyceride AbsorptionTriglyceride Absorption

2 Fatty Acid

+Monoglyceride

Triglyceride

Phospholipid AbsorptionPhospholipid Absorption

Phospholipid

Fatty Acid

+Lysophospholipid

Chylomicron FormationChylomicron Formation

WithapoB48 Cholesteryl

Triglyceride

Phospholipid

Acetyl-CoA Based MetabolismAcetyl-CoA Based Metabolism

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

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

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

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

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

Synthesis of TriacylglycerolSynthesis of Triacylglycerol

Intracellular Fatty acid MetabolismIntracellular Fatty acid Metabolism

Mobilization of Stored Fats: LipolysisMobilization of Stored Fats: Lipolysis

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

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

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

KETOGENESISKETOGENESIS

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

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

Cholesterol SynthesisCholesterol Synthesis

Cholesterol BalanceCholesterol Balance

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)

LiverSynthesisSynthesis

0.4 g/d0.4 g/d

SecretionSecretion24 g/d24 g/d

Enterohepatic Circulation of Bile SaltsEnterohepatic Circulation of Bile Salts

FecalFecalexcretionexcretion(1.2 g/d)(1.2 g/d)

(0.4 g/d)(0.4 g/d)

AbsorptionAbsorption~50%~50%

CMapoB48

LiverBiliary Biliary

Cholesterol Cholesterol (2 g/d)(2 g/d)

Biliary and Dietary CholesterolBiliary and Dietary Cholesterol

Cholesterol BalanceCholesterol Balance

CholesterolCholesterol

CholesterolCholesterol(1.2 g/d)(1.2 g/d)

++Bile SaltsBile Salts(0.4 g/d)(0.4 g/d)

(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)——

(0.4 g/d)(0.4 g/d)

LossLoss(1.6 g/d)(1.6 g/d)

——DietaryDietary

SynthesisSynthesis(1.2 g/d)(1.2 g/d)

Inhibitors of Cholesterol Synthesis Inhibitors of Cholesterol Synthesis

and Absorptionand Absorption

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

LDLLDLReceptorReceptor

StatinsStatins

Acetate

LDLLDLLDLLDL

HMG-CoAReductase

Cholesterol

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

Plant Sterols and StanolsPlant Sterols and Stanols

Sterol/StanolSterol/StanolSterol/StanolSterol/StanolDietaryDietaryCholesterolCholesterol

Plant Sterols and StanolsPlant Sterols and Stanols

Cholesterol

CholesterylEster ABCG5/G8

ACAT NPC1L1

EzetimibeEzetimibe

Cholesterol

NPC1L1

CholesterylEster ABCG5/G8

Ezetimibe

CholesterylEster

CMapoB48

Triglyceride

CMapoB48

CM RemnantapoB48

VLDLapoB100

EzetimibeXX

LDLapoB100

Dual InhibitionDual Inhibition

Assembly and Secretion of VLDLAssembly and Secretion of VLDL

Presence of TriglyceridesPresence of Triglycerides

MTPMTP

Cholesteryl Esters

Cholesterol

Dietary/Biliary Synthesis

Effect of Cholesterol Absorption InhibitorEffect of Cholesterol Absorption Inhibitor

Cholesterol

EzetimibeXX

MTPMTP

Cholesteryl Esters

Adding a Statin Blocks Compensatory Increase in Adding a Statin Blocks Compensatory Increase in SynthesisSynthesis

Cholesterol

EzetimibeXX XX Statin

MTPMTP

Cholesteryl Esters

Dual InhibitionDual Inhibition

CMapoB48

CM RemnantapoB48

VLDLapoB100

EzetimibeXX

LDLapoB100

XXStatinStatin

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

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 !

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!

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

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

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

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

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)

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

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

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

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

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

Metabolism of Metabolism of Amphipathic LipidsAmphipathic Lipids

Phospholipid SynthesisPhospholipid Synthesis

Conversion of Phosphatidylethanolamine to Conversion of Phosphatidylethanolamine to phosphatidylcholinephosphatidylcholine

Metabolism of Metabolism of Unsaturated Fatty AcidsUnsaturated Fatty Acids

Desaturation of Stearoyl-CoADesaturation of Stearoyl-CoA

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

PPAR activity

regulation of gene expression

Apoproteins of lipoproteinsEnzymes of CHO & lipid metabolism

Free fatty acids

Insulin resistance

Complement 3

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

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

PPAR activity

regulation of gene expression

Apoproteins of lipoproteinsEnzymes of CHO & lipid metabolism

glitazone, fibrates, statins PUFA (omega-3 ?)

Free fatty acids

Insulin resistance

Complement 3

LipoProteinsLipoProteins

Lipid Metabolism by Dr. de Villa

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