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

Dietary TG CE cholesterol Apo B48

Liver

Apo B48 TG A CIII

CII

FFA micelle

FFA-FABP

TG/CE

chylomicron ER/golgi enterocyte

Plasma

Type
B48

Association
Chylomicron

Function
Carry cholesterol esters Lacks LDL recpt binding domain Binds LDL recpt. Activates LPL Inhibits LPL Binds LDL recpt LCAT activator (lecithin:cholesterol acyltransferase)

B100 C-II C-III E A-1

VLDL,IDL,LDL Chyl. VLDL, IDL, HDL Chyl. VLDL, IDL, HDL Chyl. Remnant, VLDL, IDL HDL HDL/Chylomicron

Plasma B48 TG/CE FFA CII Lipoprotein Lipase TG Oxidation muscle

CIII

chylomicron

FFA

Lipoprotein Lipase CIII

B48 TG/CE E

CII

FFA G3P Triglyceride storage adipose

Chylomicron remnant

liver

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

Capillary endothelium B48 TG/CE (+) CII LPL CIII insulin

chylomicron

FFA

glut4

Glucose (+) Insulin regulated glucose transport

CoA G3P Fatty acyl CoA

adipose

Triglycerides

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

Capillary endothelium B48 TG/CE (-) CII LPL CIII FFA-albumin (oxidation) insulin

chylomicron

FFA

Glucose (-) glut4 Insulin regulated glucose transport

CoA G3P Fatty acyl CoA

adipose

Triglycerides

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

LPL synthesis and activity (adipocytes) LPL synthesis and activity (muscle)

Lactating Mammary gland

LPL activity

Plasma

Dietary Carbohydrate

LIVER

glucose B48 TG/CE CMr cholesterol (exogenous) FFA FFA E LDL receptor

pyruvate Acetyl CoA

Acetyl CoA

mitochondria TG 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

LIVER

glucose

pyruvate Acetyl CoA

Acetyl CoA

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

FFA

VLDL

VLDL

From liver

Cholesterol. In bile

LIVER Endogenous cholesterol

B100 E CE/TG VLDL CII

B100 E CE/TG IDL E B100 CE LDL

LDL receptor

LPL FFA muscle

FA

Extrahepatic tissue LDL receptor

adipose

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 1. Cholesterol to liver A HDL

Cholesterol to other lipoproteins

Liver

3. Cholesterol-ester transfer protein (CETP)

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

Cholesterol from Liver and intestinal Cells via ABCA1

CETP exchanges cholesterol esters in HDLs for triglycerides in B100 LPs

VLDL CE FFA CETP LPL TG TG CETP CE LPL FFA Liver (LDL receptor) LDL HDL

Liver (LDL receptor)

IDL

TG CETP CE

Reverse Cholesterol Transport: Indirect

Extrahepatic tissues Cholesterol esters hydrolysis Free cholesterol ABCA1 A Pre- -HDL LCAT A HDL CETP Cholesterol to VLDL, IDL,LDL Direct Liver
Cholesterol is reused or excreted in bile

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 High CARB Insulin (+) Dietary Fat Intestinal Epithelium

VLDL

(+) FA/TG

Acetyl CoA

(+)

Glucose

Liver Dietary fat Bile salts

Endogenous cholesterol Exogenous cholesterol

LDL

small intestine

extrahepatic tissue

HDL chylomicrons chylomicrons reminants VLDL IDL

capillaries Lipoprotein Lipase FFA Lipoprotein Lipase Adipose, muscle FFA

Atherogenic Particles

MEASUREMENTS:

Apolipoprotein B Non-HDL-C

VLDL

VLDLR

IDL

LDL

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

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) LDL vascular endothelium differentiate (+) Oxidized LDL

Cholesterol to liver

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

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