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

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
Lysophospholipid + FA =

Phospholipid

TAG

Reverse Cholesterol Transport via HDL

Peripheral
Tissues

Blood

Excess
Cholesterol

Liver

Bile

Cholesterol Catabolism into Bile Salts

Cholesterol

Cholate
OH
COO -

HO

HO

Cholesterol
7-hydroxylase

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

Bile

Sinusoidal Membrane

ABCG5/G8
Cholesterol

ABCB4
Phospholipid

ABCB11
Canalicular Membrane

Bile Salt

Biliary Lipids

Lipid Class

Daily Secretion (g)

Bile salts

24

Phospholipids

11

Cholesterol

Biliary Lipid Transport

Liver
Biliary
Transport
and
Storage

Duodenum

Jejunum

Ileum
Colon

Fat Digestion
Liver
Biliary
Transport
and
Storage

Duodenum

Jejunum

Ileum
Colon

Digestion
IIIIII
III
Triglycerides

II

Fatty Acids +
Monoglycerides
II
II I II
I
I
I

Dietary
Cholesterol

II
I

II
I

II
I

Fat

II
II I I
I I
I

Phospholipids
Fatty Acids +
Lysophospholipid
II
I

Fat Absorption
Liver
Biliary
Transport
and
Storage

Duodenum

Jejunum

Ileum
Colon

Cholesterol Absorption

Cholesterol
ACAT

Cholesteryl
Ester

Enterocyte

Lymph

Intestinal
Lumen

Triglyceride Absorption

2 Fatty Acid

Intestinal
Lumen
I

Enterocyte

+
Monoglyceride
DGAT

Triglyceride

Lymph

Phospholipid Absorption

Enterocyte

Fatty Acid

+
Lysophospholipid

Phospholipid

Lymph

Intestinal
Lumen

Chylomicron Formation

Lymph

Enterocyte
Phospholipid
Triglyceride

With
apoB48

Cholesteryl
Ester

Intestinal
Lumen

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

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 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 Acids

Fatty acid synthase: a

multienzyme complex
Substrate: AcetylCoA

Carbons 15 and 16 of palmitic

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

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

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 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

KETOGENESIS

Utilization 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-CoA

Cholesterol Synthesis

Cholesterol Balance

Enterohepatic Circulation of Bile Salts

Liver

Synthesis
0.4 g/d
Secretion
24 g/d

Duodenum

Biliary
Transport
and
Storage
Portal
Venous Return
(>95% of Biliary
Secretion)

Jejunum

Ileum
Colon

Fecal
Fecal
excretion
excretion
(0.4
(0.4 g/d)
g/d)

Biliary and Dietary Cholesterol

Liver

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

Biliary
Cholesterol
(2 g/d)

Duodenum

Biliary
Transport
and
Storage

Jejunum

CM
apoB48

Ileum
Absorption
Absorption
~50%
~50%

Colon

Fecal
Fecal
excretion
excretion
(1.2
(1.2 g/d)
g/d)

Cholesterol Balance
Dietary
Dietary
Cholesterol
Cholesterol
(0.4
(0.4 g/d)
g/d)

Liver

Synthesis
(1.2 g/d)

Loss
Loss
(1.6
(1.6 g/d)
g/d)

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

Cholesterol
Bile salts

Duodenum

Biliary
Transport
and
Storage

Jejunum
Ileum

Loss
(1.6 g/d)

Colon

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

Cholesterol
ACAT

Cholesteryl
Ester

NPC1L1

ABCG5/G8

Intestinal
Lumen

Ezetimibe
Lymph

Enterocyte

Cholesterol
ACAT

Cholesteryl
Ester

Intestinal
Lumen
Ezetimibe

NPC1L1

ABCG5/G8

Cholesterol Absorption Inhibitors

Lymph

CM
apoB48

Enterocyte

Triglyceride

Cholesteryl
Ester

Intestinal
Lumen

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

Cholesterol

Ezetimibe

Dietary/Biliary

Synthesis

Adding a Statin Blocks Compensatory Increase in

Synthesis
Presence of Triglycerides

MTP
ApoB

MTP
Cholesteryl Esters

Cholesterol

Ezetimibe

Dietary/Biliary

Statin

Synthesis

Dual Inhibition
LDL
apoB100

Liver

Statin

Duodenum

X
VLDL
apoB100

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

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 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 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

Enzymes of CHO & lipid metabolism

Apoproteins of lipoproteins

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

glitazone, fibrates, statins

PUFA (omega-3 ?)

Free fatty acids

PPAR activity
Complement 3
Free fatty acid uptake
Insulin resistance

regulation of gene expression

Enzymes of CHO & lipid metabolism

Apoproteins of lipoproteins

LipoProteins