Review

• ACC regulation– Covalent– Allosteric– Transcriptional

• FAS pathway– Dietary/Hormonal – Learn chemical reactions

Transport of Fat: Lipoproteins

Stipanuk 351-364

I. ChylomicronsII. Triglyceride storage in adiposeIII. VLDL, LDL, IDL, HDLIV. Reverse Cholesterol TransportV. Medical implicationsVI. Nutritional regulation of lipoproteins

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

Gordon et al. Trends in Cell Biology 5:1995

Lipid exchange protein

Heterodimer (55 kDa/97 kDa)

Protein disulphide isomerase

Defects in MTP

Abetalipoproteinemia

• Rare genetic disease

• No apo-B containing lipoproteins in plasma

• Cholesterol is ~25% of normal

• Mutation in MTP

Dietary TG

FFA FFA-FABP

micelle

enterocyte

ER/golgi

Apo B48

TGTG/CE

Apo B48

chylomicron

cholesterol

CE

Plasma

Liver

CII

CIII

A

B48 Chylomicron Carry cholesterol estersLacks LDL recptbinding 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 recptHDL

A-1 HDL/Chylomicron LCAT activator(lecithin:cholesterol

acyltransferase)

Type Association Function

TG/CE

B48

LipoproteinLipase

Plasma

FFA

FFA

G3P

Triglyceridestorage

CII

adipose

TG/CE

B48 CII

muscle

LipoproteinLipase

FFA

chylomicron

Chylomicron remnantliver

CIII

CIII

Oxidation

TG

E

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

FFA

adipose

Glucose

InsulinregulatedglucosetransportCoA

Fatty acyl CoAG3P

Triglycerides

TG/CE

B48CII

CIII

LPL

Capillary endothelium

insulin(+)

(+)glut4

chylomicron

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

FFA

adipose

Glucose

InsulinregulatedglucosetransportCoA

Fatty acyl CoA

G3P

Triglycerides

TG/CE

B48CII

CIII

LPL

Capillary endothelium

insulin(-)

(-)

glut4

chylomicron

FFA-albumin (oxidation)

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)

Fasted/ -exercisestate

LPL synthesis and activity (muscle)

LPL synthesis and activity (skeletal and heart muscle)

LPL synthesis and activity (adipocytes)

Lactating -Mammary gland

LPL activity

TG/CE

B48

cholesterol(exogenous)

CE/TG

B100

Dietary Carbohydrate

glucose pyruvate Acetyl CoA

mitochondriaAcetyl CoA

TG

FFA FFA TG VLDL

LIVER

VLDL

CMr Cholesterol(endogenous)

E

LDL receptor

Plasma

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

cholesterol(exogenous)

CE/TG

B100

Dietary Carbohydrate

glucose pyruvate Acetyl CoA

mitochondriaAcetyl CoA

TG

FFA FFA TG VLDL

LIVER

VLDL

Cholesterol(endogenous)

Plasma

CE/TG

B100

VLDL

E

CII

From liver

LPL

FFA

adiposemuscle

CE/TG

IDL

B100 ELDL receptor

CE

LDL

E

FA

B100

LIVER

Endogenous cholesterol

Extrahepatic tissue

Cholesterol.In bile

LDL receptor

Nobel Prize Alert: 1985

Michael S. Brown Joseph Goldstein

A Receptor-Mediated Pathway for Cholesterol Homeostasis 

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

Liver

ApoA

Pre--HDL

Discoidal/lipid poor

Cholesterol fromLiver and intestinal Cells via ABCA1

Pre--HDL

A A

Unesterified cholesterol-rich

Lecithin-cholesterol acyltransferase (LCAT)

HDL

1. Cholesterol to liver

Steroidogeniccells

2. Cholesterol for steroid synthesis

Cholesterolto otherlipoproteins

3. Cholesterol-estertransfer protein(CETP)

A

VLDL

IDL

LDL

LPL

LPL

FFA

FFA

Liver(LDL receptor)

Liver(LDL receptor)

HDL

CETP

CE

TG

CETP

TG

CE

CETP

TG

CE

CETP exchanges cholesterol esters in HDLs for triglycerides in B100 LPs

CETPLCAT

Free cholesterol

hydrolysis

Reverse Cholesterol Transport: Indirect

Extrahepatic tissues

Cholesterol esters

Pre--HDL

A

HDLACholesterol to VLDL, IDL,LDL

LiverCholesterol is reusedor excreted in bile

ABCA1

Direct

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

Exchange of cholesterol for VLDL TG in HDL (CETP)

Transfer of cholesterol from cells into plasmareverse transport of cholesterol from peripheral tissue to liver

LCAT activity = esterification of free cholesterol (HDL)

These postprandial changes are beneficial in maintainingwhole body homeostatsis of glycerides and cholesterol

Dietary Regulation of Lipoprotein Synthesis

Intestinal Epithelium

Chylomicron

Dietary Fat

(+)

Chylomicron Synthesis VLDL Synthesis (Liver)

Glucose

VLDLHigh CARBInsulin

(+)

Acetyl CoA

FA/TG

(+)

Dietary fat

smallintestine

capillaries

Lipoprotein Lipase

FFAAdipose, muscle

chylomicronschylomicronsreminants

VLDL

Lipoprotein Lipase

FFA

extrahepatictissue

IDL

HDL

LDL

Endogenouscholesterol

Exogenous cholesterol

Bile salts

Liver

Atherogenic ParticlesAtherogenic Particles

Apolipoprotein BApolipoprotein B

Non-HDL-CNon-HDL-CMEASUREMENTS:MEASUREMENTS:

TG-rich lipoproteinsTG-rich lipoproteins

VLDLVLDL VLDLVLDLRRIDLIDL LDLLDL Small,Small,

densedenseLDLLDL

Thanks to Lipids Online: http://www.lipidsonline.org/

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

Hypertriglyceridemia and CHD Risk: Associated Abnormalities

Relationship between HDL/LDL and heart disease:One Theory

Monocyte (white blood cell)

vascular endothelium

Arterial intima

Macrophage

Oxidized LDL(+)

LDL

LDL (+)

Foam cells (fatty streak)

(-) HDL

Cholesterol to liver

differentiate

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:819–8222. McConnell MV et al. Am J Cardiol 1997;80:1226–1228

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