-Today: Lipoproteins
-Friday: Quiz, b-oxidation and some paper discussion
-Monday: Dr. Neile Edens Guest Lecture
-Read McGary review before lecture
Transport of Fat: Lipoproteins
I. Chylomicrons
II. Triglyceride storage in adipose
III. VLDL, LDL, IDL, HDL
IV. Reverse Cholesterol Transport
V. Medical implications
VI. Nutritional regulation of lipoproteins
Stipanuk 351-364
Overview
• Transport dietary lipids from intestine to liver
(exogenous)
• Transport lipids from liver to peripheral tissues
(endogenous)
• Lipoproteins
– Core of TG and CE
– Surface of phospholipids and some cholesterol
– Apolipoproteins (regulators of LP metabolism)
– CM, VLDL, IDL, LDL, HDL
• Clinical importance for disease
Liver
Dietary TG
CE Apo B48
cholesterol
Apo B48
CII
FFA FFA-FABP TG
TG/CE
micelle
E
CIII
chylomicron
ER/golgi
enterocyte
Plasma
Chylomicron Assembly
-assembled in enterocyte golgi/ER
-Apolipoprotein (Apo) B organizes assembly
-B48
- Requires phospholipids
-2 forms of apo B
-B100, large- liver
-B48, smaller – intestine
- Picks up apo C and apo E in plasma
- TG composition closely resembles dietary intake
I. Synthesis of apoB
II. ApoB associates with
lipids
PDI (protein disulfide isomerase)
and MTP (microsomal TG transfer
protein) aid in LP folding and TG
addition
No MTP = No LP release
(a-betalipoproteinemia)
III. Lipoprotein release
IV. If not enough TG associates with
lipoprotein a protease removes apoB
and prevents its secretion
V. If lipoprotein is not properly formed
protease also can remove apoB and
prevent lipoprotein secretion
Major Lipoproteins Apolipoproteins Density (g/mL)
Apo B-48: chylomicrons C-II, C-III, E 1.21
alpha-HDL A-II 1.063-1.21
Density inversely proportional to lipid content
Type Association Function
B48 Chylomicron Lacks LDL recpt
binding domain
B100 VLDL,IDL,LDL Binds LDL recpt.
C-II Chyl. VLDL, IDL, HDL Activates LPL
C-III Chyl. VLDL, IDL, HDL Inhibits LPL
E Chyl. Remnant, VLDL, IDL Binds LDL recpt
HDL
A-1 HDL LCAT activator
(lecithin:cholesterol
acyltransferase)
Plasma
TG
B48 FFA
Oxidation
CII
muscle
TG/CE Lipoprotein
CIII Lipase
chylomicron
Lipoprotein B48 CII
FFA Lipase
TG/CE
CIII
FFA E
Chylomicron remnant
G3P liver
Triglyceride
adipose
storage
Fat accumulation in adipose: High I/G (Fed)
Capillary endothelium
(+)
B48 insulin
CII
LPL LPL deficiency?
TG/CE
CIII
chylomicron FFA Glucose
glut4
(+) Insulin
regulated
glucose
CoA transport
G3P
Fatty acyl CoA
Triglycerides
adipose
Fat accumulation in adipose: Low I/G (ketogenic)
Capillary endothelium
(-)
B48 insulin
CII
LPL
TG/CE FFA-albumin (oxidation)
CIII
chylomicron FFA Glucose
(-) Insulin
glut4 regulated
glucose
CoA transport
G3P
Fatty acyl CoA
Triglycerides
adipose
Regulation of Lipoprotein Lipase
Fed state - LPL synthesis (adipocytes)
Fasted/ -
LPL synthesis (muscle)
exercise
state
Dietary factors affecting Chylomicron and Chylomicron remnant clearance
-elevated postprandial lipoproteins and cardiovascular disease
-Diets rich in PUFA can reduce postprandial TG response
-compared to diets rich in SFA
-Increased LPL activity = Increased TG clearance from CM
-Preferential hydrolysis of PUFA-containing CM
-Increased clearance of CMr
-Human data are less convincing than animal studies
-Omega 3 CE)
• Regulated by SREBP
monitors free cholesterol
Free cholesterol = LDL receptors, chol. synthesis
ACAT
Plasma
Dietary Carbohydrate
LIVER
glucose pyruvate Acetyl CoA
Acetyl CoA
mitochondria
cholesterol
(exogenous) TG
Cholesterol
(endogenous)
B100
CE/TG VLDL
FFA FFA TG
VLDL
From liver Cholesterol.
In bile LIVER
Endogenous cholesterol
B100 E
CII
CE/TG
VLDL B100 E
LDL receptor
CE/TG
IDL E
B100
LPL TG CE
FFA LDL Extrahepatic tissue
muscle adipose LDL receptor
HDL and Reverse Cholesterol
Transport
Lipid poor AI are the
Liver and small intestine smallest HDLs (liver and SI)
Discoidal HDL are produced
Lipid poor AI by the action of LCAT
(pre HDL) (esterify cholesterol)
spherical Spheroidal HDLs are
produced by the further action
Cholesterol of LCAT and CETP (tranfer
cholesterol to LP for TG)
LCAT
LCAT HDLs pick up apoproteins from
CETP
other LP
Discoidal HDL
HDL picks up free cholesterol from Extrahepatic tissue/cells
peripheral tissues and converts it into
cholesterol esters
Cholesterol esters
LCAT acat
Free cholesterol
Cholesterol and lecithin (phospholipid)
Extracellular space
LCAT
AI HDL Discoidal HDL
AI
1
HDL/Cholesterol
To liver 2 CETP
3
Cholesterol to IDL,
Adrenal, gonadal LDL and VLDL
PLASMA
CETP exchanges cholesterol esters in HDLs for triglycerides in VLDLs and
chylomicrons.
VLDL
CE
CETP
FFA
LPL TG
Liver IDL TG
(LDL receptor) HDL
CETP
CE
LPL
FFA TG
CETP
Liver
CE
(LDL receptor)
LDL
Extrahepatic tissue/cells
1. LCAT deficiency?
2. CETP deficiency? CE
3. apo AI deficiency? ACAT
FC
Cholesterol and lecithin (phospholipid)
Extracellular space
LCAT
Pre b HDL Discoidal HDL
AI
1
HDL/Cholesterol
To liver 2 CETP
3
Cholesterol to IDL,
Adrenal, gonadal LDL and VLDL
PLASMA
Reverse cholesterol transport: HDLs return cholesterol to liver
LCAT
FC
Free Discoidal HDL CE Spherical HDL
cholesterol
TG
Peripheral tissue AI HDL
CETP
IDL CE VLDL CE VLDL TG
liver
Bile acids/Free cholesterol
LDL
Dietary fat Bile salts Endogenous
Cholesterol
extrahepatic
small Exogenous tissue
intestine cholesterol
HDL
chylomicrons
chylomicrons reminants
VLDL
IDL
capillaries
Lipoprotein Lipase Lipoprotein Lipase
FFA FFA
Adipose, muscle
Dietary Regulation of Lipoprotein
Synthesis
Chylomicron Synthesis VLDL Synthesis (Liver)
Chylomicron VLDL (+)
High CARB FA/TG
Insulin
(+)
Acetyl CoA
Dietary Fat
Intestinal Epithelium
(+)
Glucose
Atherogenic Particles
Apolipoprotein B
MEASUREMENTS:
Non-HDL-C
VLDL VLDLR IDL LDL Small,
dense
LDL
TG-rich lipoproteins
Thanks to Lipids Online: http://www.lipidsonline.org/
Hypertriglyceridemia and CHD Risk:
Associated Abnormalities
Accumulation of chylomicron remnants
Accumulation of VLDL remnants
Generation of small, dense LDL-C
Association with low HDL-C
Increased coagulability
- plasminogen activator inhibitor (PAI-1)
- factor VIIc
- Activation of prothrombin to thrombin
Relationship between HDL/LDL and heart disease:
One Theory
Monocyte (white blood cell)
Cholesterol to liver
LDL
vascular endothelium
(+)
differentiate Oxidized LDL
Arterial intima
Macrophage
LDL (+) (-) HDL
Foam cells (fatty streak)
Alcohol Increases HDL-C Level
• Alcohol increases HDL-C level in a dose-dependent
manner.
• Half bottle of wine per day (39 g alcohol) for 6 weeks
significantly increased mean HDL-C level by 7 mg/dL
in 12 healthy subjects.1
– Wine intake did not significantly affect Total-C,
Total-TG, or LDL-C.1
• One beer per day (13.5 g alcohol) for 6 weeks
significantly increased mean HDL-C level by 2 mg/dL
in 20 healthy subjects.2
– Beer intake did not significantly affect LDL-C,
VLDL-C, TG, or apolipoproteins.
1. Thornton J et al. Lancet 1983;ii:819–822
2. McConnell MV et al. Am J Cardiol 1997;80:1226–1228
Postprandial Changes in Plasma
Lipid Metabolism
Fat storage via LPL
Transfer of cholesterol from cells into plasma
reverse transport of cholesterol from peripheral tissue to liver
Exchange of cholesterol for VLDL TG in HDL (CETP)
LCAT activity = esterification of free cholesterol (HDL)
These postprandial changes are beneficial in maintaining
whole body homeostatsis of glycerides and cholesterol
Cholesterol levels are regulated
• 1. Synthesis : HMG CoA reductase
• 2. LCAT/ACAT : Free cholesterol
• 3. LDL receptor levels
• 4. Reverse cholesterol transport
• 5. Dr. Allred will discuss further