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LIPID METABOLISM

Romulo de Villa, MD, PhD, Cert. Biochem.


Molecular & Nutritional Oncologist Professor of Biochemistry & Nutrition Molecular Biology & Biotechnology Consultant

Overview
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.)
Phospholipid Metabolism Glycolipid Metabolism Metabolism of Prostaglandins and

Related compounds

Cholesterol Metabolism
Blood Lipoproteins

Digestive Lipid Metabolism


Emulsification of Dietary lipids in the small intestines

- emulsification inc. the surface area

lipase activity
- detergent property of bile salt and peristalsis
> Pancreatic activity

A. Hormonal Control of Lipid Digestion 1. CCK/pancreozymin (+)GB contraction and release of bile; release of pancreatic enzymes; dec. gastric motility 2. Secretin - (+) bicarbonate secretion

1. Triacyglycerol hydrolysis - TAG are acted upon by pancreatic lipase and removes FA at carbon 1 and 3

- products = 2-monoacylglycerol + FA
2. Cholesteryl ester degradation - Cholesterol esterase

- Products: Cholesterol + FA
3. Phospholipids degradation - phospholipase A2 - products: lysophospholipid + FA

Absorption of Lipids by intestinal mucosal cells - FFA, free cholesterol, 2-monoacylglycerol and lysophospholipid together with bile salts from

mixed micelles which is absorbed at the brush


border membrane of SI - short and medium chain FA are directly absorbed > Resynthesis of TAG, CE and PL 2-monoacylglycerol + fatty acyl-CoA = Cholesterol + FA = CE Phospholipid Lysophospholipid + FA = TAG

Reverse Cholesterol Transport via HDL Peripheral Tissues Blood Liver

Excess Cholesterol

Bile

Cholesterol Catabolism into Bile Salts

Cholesterol

Cholate
OH
COO -

HO

Cholesterol 7-hydroxylase

HO

OH

Bile Salts
Breakdown products of cholesterol Amphipathic molecules Function to transport cholesterol in the

digestive system

Structure of Biliary and Intestinal Micelles

Cholesterol
Bile Salt Phospholipid

Functions of Micelles
Transport cholesterol from the liver into

the intestine via the biliary tree

Participate in fat digestion and absorption

Biliary Lipid Secretion Blood Hepatocyte


Sinusoidal Membrane

Bile

ABCG5/G8 Cholesterol

ABCB4 Phospholipid

ABCB11
Canalicular Membrane

Bile Salt

Biliary Lipids

Lipid Class
Bile salts Phospholipids Cholesterol

Daily Secretion (g)


24 11 2

Biliary Lipid Transport


Liver Biliary Transport and Storage Duodenum

Jejunum

Ileum Colon

Fat Digestion
Liver Biliary Transport and Storage Duodenum

Jejunum

Ileum Colon

Fat

Digestion I II I II I II Triglycerides Fatty Acids + Monoglycerides I

Dietary Cholesterol

Phospholipids Fatty Acids + Lysophospholipid I I I

I I I

I I I

I I I I I I

Fat Absorption
Liver Biliary Transport and Storage

Duodenum

Jejunum

Ileum Colon

Cholesterol Absorption

Lymph

Enterocyte

Intestinal Lumen

Cholesterol
ACAT

Cholesteryl Ester

Triglyceride Absorption

Lymph

Enterocyte

Intestinal Lumen

2 Fatty Acid

+
Monoglyceride
DGAT

Triglyceride

Phospholipid Absorption

Lymph

Enterocyte

Intestinal Lumen

Fatty Acid

+
Lysophospholipid

Phospholipid

Chylomicron Formation

Lymph

Enterocyte
Phospholipid Triglyceride

Intestinal Lumen

With apoB48

Cholesteryl Ester

Acetyl-CoA Based Metabolism

De Novo Synthesis of Fatty Acids


Production of Acetyl CoA

Carboxylation of Acetyl CoA


Fatty acid synthase: a multienzyme

complex
AcetylCoA-ACP transacylase MalonylCoA-ACP transacylase

-ketoacyl-ACO synthase
Palmitoyl thioesterase

De Novo Synthesis of Fatty Acids


Production of
Translocation of

Acetyl CoA

mitochondrial citrate to cytosol


Conversion of citrate

to acetyl CoA + oxaloacetate by citrate lyase


Requirement: Inc. ATP

and Citrate

De Novo Synthesis of Fatty Acids


Carboxylation of

acetyl CoA to malonyl CoA


acetylCoA carboxylase

Carboxylation of AcetylCoA

Regulators of

to malonylCoA by AcetylCoA carboxylase


acid synthesis

Rate limiting step in fatty

Activators:

Coenzyme: Biotin insulin,Inc. CHO intake, fat-free diet Inhibitors: malonyl CoA, palmitoyl CoA,epinephrine, fasting, high fat diet

De 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 HMPShunt

1 AcetylCoA + 7 malonylCoA + 14 NADPH+ 14 H Palmitic acid + 7 CO2 + 6H2O+ Co-A-SH +14 NADP

De Novo Fatty Acid Synthesis


1. AcetylCoA + ACP-SH AcetylCoA-ACP-transacylase Acetyl-S-ACP + CoA

2. Acetyl-S-ACP + Enzyme SH
3. MalonylCoA + ACP-SH

Acetyl-S-enzyme + ACP-SH

Malonyl-ACP Transacylase Malonyl-S-ACP + CoA

4. Malonyl-S-ACP + Acetyl-S-enzyme -ketoacyl-ACO synthase Acetoacetyl-SACP + 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 Triacylglycerol

Synthesis of Triacylglycerol

Intracellular Fatty acid Metabolism

Mobilization of Stored Fats: Lipolysis

Beta-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 -OXIDATION


From PalmitoylCoA

ATP Yield 21 14 96 131 ATP 2 ATP

7NADH x 3 ATP by ETC oxidation 7 FADH2 x 2 ATP by ETC oxidation 8 Acetyl CoA x 12 ATP via Krebs CAC Total (Gross) Less

NET

129 ATP

From one molecule of palmitoylCoA

Ketone 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


Skeletal muscles Cardiac muscles

Extrahepatic tissues that can utilize Ketone bodies

Renal cortex
Brain

KETOGENESIS

Utilization of Ketone Bodies


Liver produces Ketone bodies Increased Ketogenesis

Liver cannot use acetoacetate as fuel ( lacks thiophorase : enzyme for the conversion of acetoacetate to acetoacetylCoA
to 2 acetylCoA which are oxidized by the TCA

Conditions
Starvation Severe DM Rapid mobilization

of fat
Result to ketonemia

AcetoacetylCoA is converted

ketoacidosis

Conversion of Ketone Bodies to Acetyl-CoA

Cholesterol Synthesis

Cholesterol Balance

Enterohepatic Circulation of Bile Salts


Liver
Synthesis 0.4 g/d Secretion 24 g/d

Biliary Transport and Storage

Duodenum

Jejunum

Portal Venous Return (>95% of Biliary Secretion)

Ileum Colon
Fecal excretion (0.4 g/d)

Biliary and Dietary Cholesterol


Liver
Biliary Cholesterol (2 g/d) Dietary Cholesterol (0.4 g/d)

Biliary Transport and Storage

Duodenum

Jejunum

CM apoB48
Absorption ~50%

Ileum Colon
Fecal excretion (1.2 g/d)

Cholesterol Balance
Synthesis (1.2 g/d)

Liver
Cholesterol Bile salts

Dietary Cholesterol (0.4 g/d)

Loss (1.6 g/d) Dietary Cholesterol (0.4 g/d)

Biliary Transport and Storage

Duodenum

Jejunum

Ileum

Loss (1.6 g/d)

Colon

Cholesterol (1.2 g/d) + Bile Salts (0.4 g/d)

Inhibitors of Cholesterol Synthesis and Absorption

Inhibitors of Cholesterol Synthesis: Statins

Inhibit synthesis of cholesterol by cells Lower LDL cholesterol

Mechanism: Promote LDL Clearance

Statins LDL Receptor


Acetate HMG-CoA Reductase

Cholesterol

LDL

Cholesterol Absorption Inhibitors


Inhibit absorption of dietary cholesterol Inhibit reabsorption of biliary cholesterol

Lower LDL cholesterol

Mechanism: Inhibit LDL Formation

Plant Sterols and Stanols Dietary Cholesterol Sterol/Stanol

Plant Sterols and Stanols Lymph Enterocyte Intestinal Lumen

Cholesterol
ACAT
NPC1L1

Cholesteryl Ester

ABCG5/G8

Ezetimibe Lymph Enterocyte Intestinal Lumen

Cholesterol
ACAT

NPC1L1

Ezetimibe

Cholesteryl Ester

ABCG5/G8

Cholesterol Absorption Inhibitors Lymph Enterocyte Intestinal Lumen

CM apoB48

Triglyceride

Cholesteryl Ester

Cholesterol Absorption Inhibitors


LDL apoB100

Liver Duodenum

VLDL apoB100

Ezetimibe

Jejunum

Ileum
CM Remnant apoB48 CM apoB48

Colon

Dual Inhibition

Assembly and Secretion of VLDL

Presence of Triglycerides

MTP ApoB

MTP
Cholesteryl Esters

Cholesterol

Dietary/Biliary

Synthesis

Effect of Cholesterol Absorption Inhibitor

Presence of Triglycerides

MTP ApoB

MTP
Cholesteryl Esters

Ezetimibe

Dietary/Biliary

Cholesterol

Synthesis

Adding a Statin Blocks Compensatory Increase in Synthesis


Presence of Triglycerides

MTP ApoB

MTP
Cholesteryl Esters

Ezetimibe

Dietary/Biliary

Cholesterol

Statin

Synthesis

Dual Inhibition
LDL apoB100

Liver Duodenum

X
VLDL apoB100

Statin

Ezetimibe

Jejunum

Ileum
CM Remnant apoB48 CM apoB48

Colon

Conclusions
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 symptom for 1/3 of all the heart attacks that occur each and every day is . . .

INSTANT DEATH !

Stress, Smoking, Lack of exercise, Poor nutrition and of course, Genetics all contribute to HEART DISEASE! But the real culprit is,

HIGH
CHOLESTEROL!

High LDL-Cholesterol is a Major Culprit for Cardiovascular Risk

Cholesterol is everywhere in the Body ?


Inside Cells

Hepatic Tissue
Extrahepatic Tissue Outside Cells Connective Tissue (Blood) Within Cell Membranes

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 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 Cholesterol

Cholesterol is brought to the liver when HDL

binds to the liver Cholesterol 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 Study
70% of men with Coronary Heart Disease (CHD) had <44

mg/dL HDL-cholesterol
1.5 % risk 7.2 % risk

if

HDL-c

> 35 mg/dL

if t-chol/HDL-c > 5 HDL-c & Trigly are low if t-chol/HDL-c > 5 HDL-c < 35 mg/dL Trigly > 200 mg/dL

11.5 % risk

The higher the HDL-c the lower the rate of CHD

Normal Ratio of t-cholesterol / HDL-c = < 5

Low Lipid Levels in Filipinos

Triglyceride Cholesterol HDL-c

116 mg/dL 159 mg/dL

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 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 Amphipathic Lipids

Phospholipid Synthesis

Conversion of Phosphatidylethanolamine to phosphatidylcholine

Metabolism of Unsaturated Fatty Acids

Desaturation of Stearoyl-CoA

Most type 2 diabetics die of heart attack.


Why is DM a risk factor for MI?

Peroxisome-Proliferator activated receptor (PPAR) links


Type 2 diabetes mellitus with heart attack
Atherosclerosis is an inflammation-based process Free fatty acids PPAR activity Complement 3 Free fatty acid uptake Insulin resistance

Most type 2 diabetics die of heart attack.


Why is DM a risk factor for MI?

Peroxisome-Proliferator activated receptor (PPAR) links


Type 2 diabetes mellitus with heart attack
Atherosclerosis is an inflammation-based process Free fatty acids PPAR activity Complement 3 Free fatty acid uptake Insulin resistance

regulation of gene expression Apoproteins of lipoproteins

Enzymes of CHO & lipid metabolism

Functions of PPAR
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

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

Most type 2 diabetics die of heart attack.


Why is DM a risk factor for MI?

Peroxisome-Proliferator activated receptor (PPAR) links


Type 2 diabetes mellitus with heart attack
Atherosclerosis is an inflammation-based process Free fatty acids PPAR activity Complement 3 Free fatty acid uptake Insulin resistance

glitazone, fibrates, statins

PUFA (omega-3 ?)

regulation of gene expression Apoproteins of lipoproteins

Enzymes of CHO & lipid metabolism

LipoProteins

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