Basics of Lipid and

Lipoprotein Metabolism
John R. Guyton, M.D.
Associate Professor of Medicine
Duke University
Durham, NC

Lipid Structure
Cholesterol

HO

Fatty Acids
COOH

COO

COOH

COO

COOH

COO

HO

Glycerol

Triglycerides

Phospholipid: Lecithin
COO

HO

COO

HO

OPOO

HMG CoA Reductase

(More Than Cholesterol Synthesis)
Acetyl CoA
HMG CoA
HMG CoA Reductase
Mevalonate

Prenylation of
signalling peptides
(ras, rho, etc.)

Isopentenyl
adenine
(transfer RNA)

Farnesyl Pyrophosphate

Dolichols

Cholesterol

Ubiquinones
(CoQ-10, etc.)

Inhibition of other key products of mevalonate may relate to

nonlipid effects & rare side effects of statins.

NORMAL CHOLESTEROL METABOLISM

0.8 G
SYN CHOL*

Tissue
pools
70G

0.4 G CHOL

*SYN CHOL = CHOLESTEROL SYNTHESIS

NORMAL CHOLESTEROL METABOLISM

0.85 G
ABS CHOL

0.8 G
SYN CHOL*

Tissue
pools
70G

1.3 G
CHOL
.20 G CHOL

0.65 G CHOL

50%
0.4 G CHOL

.20 G
.65 G

*SYN CHOL = CHOLESTEROL SYNTHESIS

NORMAL CHOLESTEROL METABOLISM

Key concepts: synthesis

Primary synthetic sites are extrahepatic, but liver
is key regulator of homeostasis

Key concepts: absorption

Largest source is biliary secretion, not diet.
Normal absorption: 50%
For cholesterol to be absorbed it must:

undergo hydrolysis (de-esterification by esterases)

be incorporated into micelles
be taken up by cholesterol transporter
be re-esterified and incorporated into chylomicrons

NORMAL CHOLESTEROL ABSORPTION

1,300mg/day
400mg/day

Oil phase

NORMAL CHOLESTEROL ABSORPTION

1,300mg/day
400mg/day

Oil phase

17,400mg/day

Plant sterols compete

For cholesterol here

STRUCTURE OF PLANT STEROL

ESTERS
Cholesterol
Sitosterol
HO

HO

O
C-O

Sitosterol Ester

NORMAL CHOLESTEROL ABSORPTION

1,300mg/day
400mg/day

Oil phase

17,400mg/day

850mg/day

Ezetimibe competes
For cholesterol here

NORMAL CHOLESTEROL ABSORPTION

1,300mg/day
400mg/day

Oil phase

17,400mg/day

850mg/day

Defect in ABCG5/G8
transporter causes
phytosterolemia

NORMAL CHOLESTEROL METABOLISM

Role of Bile Salts, cholesterol, phospholipids in
gall stone formation.
Importance of Bile Salts for cholesterol absorption
Key concepts: bile salt absorption inhibitors
Bile acid binding compounds:

Welchol
Cholestyramine
Colestipol
Fiber

Surgery: Partial ileal bypass.

Bile Acid Synthesis

Cholesterol
HO
OH
COOH

COOH

OH

OH

OH

Cholic
Acid

OH

COOH

OH

Deoxycholic
Acid

OH

Chenodeoxycholic
Acid
COOH

OH

Lithocholic
Acid

NORMAL CHOLESTEROL METABOLISM

0.85 G
ABS CHOL

0.8 G
SYN CHOL

Tissue
pools
70G

1.3 G
CHOL
.20 G CHOL

0.65 G CHOL

50%
0.4 G CHOL

.20 G
.65 G

NORMAL CHOLESTEROL METABOLISM

0.85 G
ABS CHOL

0.8 G
SYN CHOL

Tissue
pools
70G

0.35 G BA*

1.3 G
CHOL

17.35 G
BA*

17 G
BA*

.20 G CHOL

0.65 G CHOL

50%
0.4 G CHOL

* BA = BILE ACIDS

95%
.20 G
.65 G
.35 G
1.20 G
CHOL + BA

NORMAL TRIGLYCERIDE METABOLISM

Key concepts: absorption

Triglyceride (i.e. energy) assimilation is key to the
survival of the organism.
Dietary triglyceride must be hydrolyzed to fatty
acids, mono-glycerides and glycerol prior to
absorption.
Fatty acids must partition to micellar phase for
absorption.
For transport, triglyceride must be reconstituted
from glycerol and fatty acid and incorporated into
chylomicrons.

Structures of Fatty Acids

O
C
HO

18:0

O
C
HO

cis-18:1 -6

O
C
HO

trans-18:1 -6

O
C
HO

18:2 -6

O
C
HO

18:3 -3

Structures of Fatty Acids

O
C
HO
O
C
HO

16:0 (palmitic)
cis-18:1 -6 (oleic)

O
C
HO
O
C
HO

trans-18:1 -6 (elaidic

O
C
HO

(alpha
18:3 -3
linolenic)

O
C
HO

18:2 -6 (linoleic)

20:5 -3 (EPA)

Fatty Acid and Triglyceride Flux

FATTY
ACIDS

(ALBUMIN)

TG (VLDL)
LIPOPROTEIN
LIPASE

TG (CHYLOMICRONS)

Dietary Carbohydrate Increases

VLDL Production

Dietary
Carbohydrate

Plasma
Triglyceride
(VLDL)

Effect of Carbohydrate Restriction on

Carbohydrate-induced
Hypertriglyceridemia
Treatment: Fast for average 5 days, then consume low CHO diet.

Composition
of diet:
7-15% CHO
25-30% Prot
60-65% Fat

Reisell et al., Am J Clin Nutr 1966;19:84

Lipoprotein
Metabolism

Cholesterol Ester
Synthesis
Acyl-Cholesterol Acyl Transferase (ACAT)
Cholesterol

COOH

Cholesterol
Ester

HO

COO

Lecithin-Cholesterol Acyl Transferase (LCAT)

Lysolecithin

COO

COO

COO

COO

OPOO

OPOO

Lipoproteins:
Separation by
Electrophoresis

Density

Size by
Electron Microscopy

Pancreatic Lipase Movement

Most
Most pancreatic
pancreatic
lipase
lipase is
is secreted
secreted
into
into the
the pancreatic
pancreatic
duct,
duct, but
but some
some moves
moves
back
back into
into capillaries.
capillaries.

Chylomicron Role in
Pancreatitis
Pancreatic
Pancreatic lipase
lipase acts
acts
on
on chylomicrons
chylomicrons
adherent
adherent to
to capillary
capillary
endothelium,
endothelium, producing
producing
fatty
fatty acid
acid anions,
anions, or
or
soaps.
soaps. By
By detergent
detergent
action,
action, cell
cell membranes
membranes
are
are disrupted,
disrupted, releasing
releasing
more
more lipase,
lipase, and
and
additional
additional fatty
fatty acid
acid
anions
anions are
are produced
produced in
in
aa vicious
vicious cycle.
cycle.

Apolipoproteins
apoA-I

HDL structural protein; LCAT activator;RCT

apoA-II

HL activation

apoA-IV

Tg metabolism; LCAT activator; diet response

apoB-100 Structural protein of all LP except HDL

apoB-48 Binding to LDL receptor
apoC-I

Inhibit Lp binding to LDL R; LCAT activator

apoC-II

LpL activator

apoC-III

LpL inhibitor; antagonizes apoE

apoE

B/E receptor ligand

*E2:IDL; *E4: Diet Responsivity

Metabolic Relationships
Among Lipoproteins
1.
VLDL

LDL

3.

2.

TG
HDL

Lipoprotein
Lipase`

 TRIGLYCERIDES

HDL

SMALL
DENSE LDL

Role of CETP in Triglyceride/

Cholesteryl Ester Exchange

TG

VLDL

CETP HDL

CE

TG
HDL CETP
CE

LDL

Role of Triglycerides in Producing

Small Dense LDL or HDL

CETP

CE
TG

Lipase

CE
TG

1. CE exchanged for TG

CE
TG

2. TG removed

Dyslipidemia of Metabolic Syndrome

FREE
FATTY
ACIDS

TG

VLDL

TG

CETP HDL CETP

CE

UNINHIBITED
LYPOLYSIS

CE

HDL
CATABOLISM

LDL

LIPASE

sdLDL

FATTY ACIDS
GLYCEROL

Cumulative percent of cases

Distribution of LDL Size Phenotypes

According to Triglyceride Levels
Phenotype A
(light fluffy LDL)

Phenotype B
(small dense LDL)

Triglyceride (mg/dl)
Austin et al, Circulation 1990; 82:495

Peroxisome Proliferator-Activated
Receptor:
A Nuclear Receptor for Metabolic
Genes

a, Basic mechanism of action of

nuclear hormone receptors: bind
to a specific sequence in the
promoter of target genes (called
hormone response elements), and
activate transcription upon
binding of ligand. Several nuclear
hormone receptors, including
the retinoic acid receptor, the
vitamin D receptor and PPAR, can
bind to DNA only as a heterodimer
with the retinoid X receptor, RXR,
as shown. b, some PPAR and
PPAR ligands.

Kersten et al. Roles of PPARs in

health
and disease. Nature 2000; 405:
421-424

Role of PPAR* and in VLDL,

LDL
and HDL metabolism
PPAR
Tissues:Liver,kidney,heart,
muscle.
Ligands:fattyacids,fibrates
Actions:Stimulateproduction
ofapoAI,lipoproteinlipase,
increaseexpressionofABC
A1,increaseFFAuptakeand
catabolism,decreaseFFA
andVLDLsynthesis.

PPAR
Tissues:Adiposetissueand
intestine.
Ligands:arachidonicacid,
Glitazones
Actions:increaseexpressionof
ABCA1,increaseFFAsynthesis
anduptakebyadipocytes,increase
insulinsensitivity(?)

*PeroxisomeProliferatorActivatedReceptor

HDL and Reverse Cholesterol

Transport

HDL and Reverse Cholesterol

Transport

Tangier Disease

HDL and Reverse Cholesterol

Transport

HDL and Reverse Cholesterol

Transport

HDL and Reverse Cholesterol

Transport

HDL and Reverse Cholesterol

Transport

LDLR

HDL and Reverse Cholesterol

Transport

LDLR

50%ofHDLCmay
Returntotheliver
OnLDLviaCETP

Lipoprotein(a), or Lp(a)
An atherogenic lipoprotein
containing apo(a) and apoB.
20-30% of people have levels
suggesting C-V risk.

Apo(a)
LDL

-S-S-

Black subjects have Lp(a)

normal range twice as high
as white and Asiatic subjects.
Apo(a) sequence similar to plasminogen, and Lp(a)
interferes with spontaneous thrombolysis.
Lp(a) levels highly genetic, resistant to diet and drug
therapy, although niacin may help.

Summary Lipid and

Lipoprotein Metabolism
Cholesterol absorption, synthesis, and
disposition
Triglyceride/fatty acid transformations and
energy metabolism
Lipoprotein core and surface components
Lipoprotein origins and destinations governed
by apos
Derangement in the metabolic syndrome
Reverse cholesterol transport the dominant
direction
Lipoprotein(a)
Lipoproteins in the arterial wall