BIOC 801 - Dr.

Tsao
Lecture 31 – March 29, 2006

LIPIDS:
BIOCHEMISTRY OF LIPIDOSES
AND ATHEROSCLEROSIS
 Clinical Defect in Clinical Defects in
(Normal digestion)
Lipid Digestion Lipid Absorption

Pancreatic lipase/colipase Bile acid Mucosal Lymphatic

deficiency (genetic-rare) deficiency disease disease
"acquired" or
liver disease; Genetic: Whipple's
"secondary": pancreatitis,
biliary Abetalipoproteinemia Disease
pancreatic carcinoma, CF
obstruction; Acquired:
Increased TAG into colon ileal resection tropical sprue
celiac sprue
Bacterial lipases

Increased FA in colon STEATORRHEA

Induced water secretion DIARRHEA

Figure 1. Fat malabsorption syndromes

►Recall consequences of cystic fibrosis (CF) discussed in protein digestion lecture
 B48
Figure 2. Site of defect
in abetalipoproteinemia X
Chylomicron
Coating with
Absence of chylomicrons, VLDLs, LDLs apolipoprotein
(TTP-transfer)
Defect of apoB protein or TTP
Short/medium chain FFA are processed Triacylglycerol
These FFA provide treatment via inclusion
in synthesized TAGs
reesterification
Lymphatic pathology (Whipple’s disease)
backs up absorption process
Mixed FFA,
Micelles: 2MG

Short/medium
chain FFA
 LDL receptor  Wolman’s disease
LDL   NPC disease
synthesis
 receptor  Tangier
(hypolipidemia)
lysosome/ NPC-1  FHC (type II)
Golgi
late endosome mediated
transfer free pool of
ACEH
CE  cholesterol
cholesterol ACAT
endocytosis  
CE stored
Cholesterol
Cholesterol release in droplets
Esterase
for transport to liver CE CE
LDL CERP induced
CE by cholesterol Cholesterol
 metabolism to bile
acids or steroids
Membrane
Apo A1 receptor
Cholesterol
C
A
L

CE in Apo A1 (activates CERP

to the liver for processing
HDL to pump cholesterol
across the membrane)
Figure 3. Disorders of cholesterol lipid storage and processing
 100 0
Figure 4. Phase diagram of the
properties of three major components
in human gallbladder bile 80
20
% Cholesterol 60 40
% Lecithin
40 60

20 80
stone
normal
0 100
100 80 60 40 20 0
Table 1. Human gallbladder bile
% Bile Salt
composition
Bile Lecithin Cholesterol
Salt
Normal 80% 15% 5%
Gallstone 68% 22% 10%
(typical)
Low bile salts lower ability to dissolve cholesterol gallstones
 VLDL cholesterol Dietary
Cholesterol synthesis via liver synthesis Cholesterol
Acetyl CoA via Circulation
LDL cholesterol
HMG-CoA A
HMG-CoA X Uptake via LDL receptor
reductase Mevalonate Intracellular Fates: esterification by
ACAT and storage;
Cellular Cholesterol
steroid hormone/ vitamin D synthesis

Esterification/removal by LCAT/HDL

CE in HDL Liver uptake

via apo E
receptor
Cholesterol B
Bile Acids X Cholesterol in liver
excretion as
(lipid absorption) partly metabolized
bile acids

Figure 5. Summary of cholesterol metabolism.

A, B represent feedback repression of these enzymes
 chylomicrons travel type I hyperlipidemia:
to capillaries adipose/muscle cannot process
chylomicrons by LPL either because
LPL or apo CII defective
Nascent
chylomicrons
mature non-hepatic tissues
N

N
T
E

E
S
I

X X XX
CE CE
CEC C
EC
E CEEC E CE
CE C
C E C E C E C E
CE CEE C EC E C E CECE
C EC E
CE
Chylomicrons are not CECE
ApoB48 helps processed by non-hepatic
with chylomicron tissues and therefore
assembly accumulate in the blood.

Figure 6. Defect in type I hyperlipidemia that is

characterized by accumulation of chylomicrons
Chylomicron

8 8 88 8 8 8
A1 Mature

B4B4BB44B4B4 B4
Remnant A1
A1
A1
A1 HDL
A1
A1 CII
CII

E E EE E E E
CII
CII
CII

E EEEEEE
CII
CII

X
X

E
E Receptor
Receptor
Lack of liver clearance of cholesterol in
type III hyperlipidemia

Figure 7. Defect in type III hyperlipidemia characterized by

accumulation of chylomicron remnants, HDLs and IDLs (not
shown) due to defective apolipoprotein E or apo E receptor.
 TYPE IV HYPERLIPIDEMIA

most common hyperlipidemia

increases in both triacylglycerol and cholesterol

not due to defects in lipoprotein processing

VLDL levels  by overproduction - obesity, alcohol abuse, diabetes

Diabetes:
cannot shutdown hormone sensitive lipase  mobilize FFA
FFA  liver  TAGs  VLDL  circulation
VLDL  pathologically excessive LDL

incidence of CAD elevated in all Type IV hyperlipidemic patients

 LDL

Oxidation of LDL

Pathogenesis

Oxidized LDL
1. Uptake by "scavenger receptors" on
macrophages that invade artery walls;
become foam cells
2. Elicits CE deposition in artery walls
3. Atherosclerosis/CAD can develop

Figure 8. Features of oxidized LDL (review)

 PGI2 TXA2

Blood Vessel Wall Endothelial Cell

Normal Physiology
Smooth Platelet
TXA2
Muscle Cell PGI2
TXA2/
TXA3 Low dose aspirin intervention favors platelet
Knocks down platelet TXA2 disaggregation

TXA3
PGI2/ PGI3
HEALTHY
PGI3
Dietary 3 fatty acid favors platelet
intervention (cold water fish) disaggregation
PGI3 activity >> TXA3

Figure 9. Control of platelet aggregation:

Suppression of platelet aggregation by drug or dietary intervention
– taken from Fig. 7, lecture 30
Figure 9. Control of platelet aggregation: Blood Vessel Wall Endothelial Cell
Injury leading to platelet aggregation Smooth Platelet
for wound healing Muscle Cell
– taken from Fig. 6, lecture 30
TXA2

HEALTHY

PGI2
Reendothelialization
Injury

Injury: catheter, injury DAMAGED

turbulence, etc.

PGI2
TXA2

Injury

Aggregated
Platelets
Blood Vessel Wall Endothelial Cell
Platelet Figure 9. Control of platelet aggregation:
Smooth
Factors leading to platelet aggregation
Muscle Cell
in atherosclerotic plaques
TXA2

HEALTHY Smoking, oxidants, or homocysteine

High BP; High dietary chol/sat fats
PGI2
Macrophage invasion

Athero-
DAMAGED
sclerosis
PGI2
TXA2
CE laden
macrophages
("foam cells") Aggregated
Platelets

CE laden smooth muscle Damaged endothelium

cells; proliferation from high BP PGI3,
stimulated by PDGF &
E-1 (suppressed by
polyphenol in red wine)
 oxidized LDL/CE
(high sat fat & chol in
diet), smoking, etc.
Blood Vessel Wall Endothelial Cell
Platelet Figure 9. Control of platelet aggregation:
Smooth
Factors leading to reversal or prevention
Muscle Cell
of platelet aggregation
TXA2/3
Partial reversal/prevention of aggregation
HEALTHY and lipid accumulation by diet (3 FA; low chol

PGI2/3 & sat fat) and drug therapy (low dose aspirin,
antiox vitamins, chol lowering drugs)
Macrophage invasion

Athero-
DAMAGED
sclerosis
PGI2
TXA2
CE laden
macrophages
("foam cells") Aggregated
Platelets

CE laden smooth muscle Damaged endothelium

cells; proliferation from high BP PGI3,
stimulated by PDGF &
E-1 (suppressed by
polyphenol in red wine)
 oxidized LDL/CE
(high sat fat & chol in
diet), smoking, etc.