Review

ACC regulation
Covalent
Allosteric
Transcriptional
FAS pathway
Dietary/Hormonal
Learn chemical reactions
 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

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 A,C and E in plasma

- TG composition closely resembles dietary intake

 Microsomal Transfer Protein

Lipid exchange protein

Heterodimer (55 kDa/97 kDa)

Protein disulphide isomerase

Defects in MTP

Gordon et al. Trends in Cell Biology 5:1995

 Abetalipoproteinemia
Rare genetic disease
No apo-B containing lipoproteins in
plasma
Cholesterol is ~25% of normal
Mutation in MTP
 Liver
Dietary TG
CE Apo B48

cholesterol
Apo B48
CII
FFA FFA-FABP TG
TG/CE
micelle
A
CIII

chylomicron
ER/golgi

enterocyte

Plasma
Type Association Function

B48 Chylomicron Carry cholesterol esters

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/Chylomicron 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
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
 LPL: Metabolic Gatekeeper?
LPL deficiency (chylomicronaemia)
Massive accumulation of chylomicron-TG in plasma
Cannot clear TG normally
- Normal fat storage and body weight ???!?!?
- How?
- Knockout mice lethal
- LPL overexpression
- Decrease plasma TG
- Increase FA uptake in skeletal muscle
- Protect against obesity when fed high-fat diet
 Hormones and Adipose Tissue

-Adipose tissue is not just a big fat depot

-Produces a number of hormones that regulate fat storage

1. Leptin decrease food intake/increase energy utilization

* Adequate fat store = release leptin = decrease food
intake and increase energy utilization

2. Acylating stimulating protein (ASP)

chylomicrons stimulate production of ASP
similar anabolic effects as insulin (different mechanisms)
Promote adipocyte glucose uptake and
FA reesterification
Ob mice
 Regulation of Lipoprotein Lipase

Fed state - LPL synthesis and activity (adipocytes)

LPL synthesis and activity (skeletal and heart muscle)

Fasted/ - LPL synthesis and activity (adipocytes)

exercise
LPL synthesis and activity (muscle)
state

Lactating -
LPL activity
Mammary
gland
Plasma
Dietary Carbohydrate
LIVER

glucose pyruvate Acetyl CoA

B48 LDL receptor Acetyl CoA

E mitochondria
TG/CE
TG
CMr Cholesterol
cholesterol (endogenous)
B100
(exogenous)
CE/TG VLDL
FFA FFA TG

VLDL
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 > Omega 6 > SFA

-Not much work with MUFA although may be helpful (OLIVE OIL)
Endogenous Lipid Transport
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 FA CE

FFA LDL Extrahepatic tissue

muscle adipose LDL receptor

 Nobel Prize Alert: 1985
A Receptor-Mediated Pathway for Cholesterol Homeostasis

Michael S. Brown Joseph Goldstein

 Function of LDL receptor
Endocytosis of LDL and other LP
Release free cholesterol into liver
1. Incorporate into plasma membrane
2. Inhibit new LDL receptors
3. Inhibit cholesterol synthesis
4. Promote ACAT activity (FC -> CE)
Regulated by SREBP
monitors free cholesterol
Free cholesterol = LDL receptors, chol. synthesis
ACAT
HDL Formation Steroidogenic
cells Cholesterol
to other
2. Cholesterol lipoproteins
for steroid
Liver synthesis 3. Cholesterol-ester
1. Cholesterol transfer protein
to liver (CETP)

A HDL

ApoA
Lecithin-cholesterol acyl
transferase (LCAT)

A A
Pre--HDL Cholesterol from
Liver and intestinal Pre--HDL
Cells via ABCA1
Discoidal/lipid poor Unesterified cholesterol-rich
CETP exchanges cholesterol esters in HDLs for triglycerides in B100 LPs

VLDL
CE

CETP
FFA
LPL TG

Liver IDL TG
(LDL receptor) HDL
CETP
CE

LPL
FFA TG
CETP
Liver
CE
(LDL receptor)
LDL
 Reverse Cholesterol Transport: Indirect

Extrahepatic tissues

Liver
Cholesterol esters Cholesterol is reused
or excreted in bile
hydrolysis
Direct
Free cholesterol

ABCA1
A
LCAT CETP Cholesterol to
Pre--HDL A HDL
VLDL, IDL,LDL
Reverse Cholesterol Transport :
Direct
SR-BI (scavenger receptor, class B, type 2)
1. LCAT deficiency?
2. CETP deficiency?
3. apo AI deficiency?
 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
 Dietary Regulation of Lipoprotein
Synthesis
Chylomicron Synthesis VLDL Synthesis (Liver)

Chylomicron VLDL (+)

High CARB FA/TG
Insulin

(+)
Acetyl CoA
Dietary Fat

Intestinal Epithelium
(+)
Glucose
 LDL
Liver

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
 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
Association with low HDL
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:819822

2. McConnell MV et al. Am J Cardiol 1997;80:12261228