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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

FFA

FFA-FABP

Apo B48
TG

micelle

CII

TG/CE
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

Chyl. Remnant, VLDL, IDL


HDL

Binds LDL recpt

A-1

HDL/Chylomicron

LCAT activator
(lecithin:cholesterol
acyltransferase)

Plasma
FFA

B48

CIII

CII

TG
Oxidation
muscle

Lipoprotein
Lipase

TG/CE

chylomicron

FFA

Lipoprotein
Lipase

B48
CIII

CII

TG/CE
E

FFA

Chylomicron remnant

G3P
Triglyceride
storage

adipose

liver

Fat accumulation in adipose: High I/G (Fed)


Capillary endothelium
(+)

B48

insulin

CII
LPL

CIII

TG/CE

chylomicron

FFA

glut4

Glucose
(+)

CoA
G3P
Fatty acyl CoA

adipose

Triglycerides

Insulin
regulated
glucose
transport

Fat accumulation in adipose: Low I/G (ketogenic)


Capillary endothelium
(-)

B48

insulin

CII
LPL

CIII

TG/CE

chylomicron

FFA-albumin (oxidation)

Glucose

FFA

(-)
glut4
CoA
G3P
Fatty acyl CoA

adipose

Triglycerides

Insulin
regulated
glucose
transport

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/ exercise
state

Lactating Mammary
gland

LPL synthesis and activity (adipocytes)


LPL synthesis and activity (muscle)

LPL activity

Plasma

Dietary Carbohydrate

glucose
B48

LDL receptor

TG/CE

LIVER

pyruvate

Acetyl CoA

Acetyl CoA
mitochondria

E
TG

CMr
cholesterol
(exogenous)
FFA

FFA

B100
TG

CE/TG

Cholesterol
(endogenous)

VLDL

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

glucose

LIVER

pyruvate

Acetyl CoA

Acetyl CoA
mitochondria
cholesterol
(exogenous)

TG
B100

FFA

FFA

TG

CE/TG

Cholesterol
(endogenous)

VLDL

VLDL

Cholesterol.
In bile

From liver

LIVER
Endogenous cholesterol

B100 E
CE/TG

CII

VLDL

B100 E

LDL receptor

CE/TG
IDL

LPL

FA

B100
CE
LDL

FFA
muscle

adipose

Extrahepatic tissue
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.
2.
3.
4.

Incorporate into plasma membrane


Inhibit new LDL receptors
Inhibit cholesterol synthesis
Promote ACAT activity (FC -> CE)

Regulated by SREBP
monitors free cholesterol
Free cholesterol =

LDL receptors, chol. synthesis


ACAT

HDL Formation

Steroidogenic
cells
2. Cholesterol
for steroid
synthesis

Liver

Cholesterol
to other
lipoproteins

3. Cholesterol-ester
transfer protein
(CETP)

1. Cholesterol
to liver
HDL

A
ApoA

Lecithin-cholesterol acyl
transferase (LCAT)
A
Pre--HDL
Discoidal/lipid poor

Cholesterol from
Liver and intestinal
Cells via ABCA1

A
Pre--HDL
Unesterified cholesterol-rich

CETP exchanges cholesterol esters in HDLs for triglycerides in B100 LPs

VLDL
CE
FFA

CETP
LPL

Liver
(LDL receptor)

TG

IDL

TG
HDL

CETP
CE
LPL

TG

FFA

CETP

Liver
(LDL receptor)

CE
LDL

Reverse Cholesterol Transport: Indirect

Extrahepatic tissues
Liver

Cholesterol esters

Cholesterol is reused
or excreted in bile

hydrolysis
Direct

Free cholesterol
ABCA1
A
Pre--HDL

LCAT

HDL

CETP

Cholesterol to
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
Insulin

(+)
FA/TG

(+)

Acetyl CoA
Dietary Fat

Intestinal Epithelium

(+)

Glucose

LDL

Liver
Dietary fat

Bile salts

small
intestine

Endogenous
cholesterol
extrahepatic
tissue

Exogenous
cholesterol

HDL
chylomicrons

chylomicrons
reminants

VLDL
IDL

capillaries
Lipoprotein Lipase

Lipoprotein Lipase
FFA

Adipose, muscle

FFA

Atherogenic Particles

MEASUREMENTS:

VLDL

VLDLR

Apolipoprotein B
Non-HDL-C

IDL

TG-rich lipoproteins
Thanks to Lipids Online: http://www.lipidsonline.org/

LDL

Small,
dense
LDL

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

Macrophage
LDL (+)

(-) HDL

Foam cells (fatty streak)

Arterial intima

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

Journal Papers and Revision


Out of 10 points
Revisions 30 pts
Clear, concise writing
Extend discussion
Additional references- email author w/ ?
and include in revised report
Current and future research

Next Week
Feb 23 Dr. Neile Edens Ross Labs
Feb 25 Beta oxidation/Cholesterol
Feb 27 Exam Review/Rough Draft
revisions