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Lipids

2000 composed of saturated,

unsaturated and/or aromatic or aliphatic hydrocarbonmoieties -Non-polar lipids

When water-binding functional groups (-OH, -COOH,

-NH, -C=O, etc.) are covalently linked -Polar Lipids Biologically-relevant lipids are molecules with

aliphatic chains of at least 12C atoms and/or

aromatic/aliphatic structures with at least 3 ringswhich may be fused

Old system of classification based on solubility in

organic solvents is neither strictly true nor useful (e.g.,bile salts)

Harvard-MIT Division of Health Sciences and Technology

HST.121: Gastroenterology, Fall 2005

Instructors: Dr. Martin Carey

Molecules of Mr =150 -

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OCTADECANOL

Graphic representations of a Polar

Lipid

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CH3

CH2

CH2

CH2

CH2

CH2

CH2

CH2

CH2

H2C

H2C

H2C

H2C

H2C

H2C

H2C

H2C

H2C

OH

AIR

Water

Lipid soluble

portion of molecule

Water soluble

portion of molecule

10 A

Figure by MIT OCW.

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Classification of Polar Lipids Based

on Interactions with H2O*

*D. M. Small (1968)

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Non-Polar Lipids

Polar Lipids

A.

B.

C.

1.

2.

with lyotropic mesomorphism

without lyotropic mesomorphism

L.C. Micelle

Micelle

Insoluble In Bulk

Bulk Phase-pure liquid crystals in pure water

Bulk Phase-a micellar solution

Bulk Phase-a micellar solution

Class Surface and Bulk Interactions with Water

Insoluble Non-Swelling Amphiphiles

Insoluble Swelling Amphiphiles

Soluble Amphiphiles

Will Not Spread To Form A Monolayer

Forms A Stable Monolayer Insoluble In Bulk

Forms A Stable Monolayer

Forms An Unstable Monolayer

Forms An Unstable Monolayer

.

Refer to: Small, D.M. "A Classification of Biological Lipids Based Upon Their Interactions in Aqueous Systems."

J Amer Oil Chem Soc45 (1968): 108-119.

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Self-Aggregated States

i) LIQUID CRYSTALS (L.C.)

Intermediate Physical States (mesophases) with

properties of both liquids and solid crystals.

Long rage order in at least 1 dimension

Have distinct optical textures by polarizing

microscopy

- Lyotropic L.C.

- Thermotropic L.C.

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OIL

OIL

Heat

Heat

Heat

CRYSTAL

CRYSTAL LAMELLAR HEXAGONAL MICELLAR SOLUTION

INSOLUBLE LIQUID CRYSTALS SOLUBLE

+H2O

-H2O

+H2O

-H2O

+H2O

-H2O

[LC]

Heat

WATER

Figure by MIT OCW.

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Self Aggregated States

ii) MICELLES

Thermodynamically stable aggregates ofsoluble amphiphilic lipids that form

spontaneously above a critical micellar

concentration (CMC) and critical micellar

temperature (CMT)

-The hydrophobic effect

-

in aqueous systems: regular micelles

in organic solvents: reverse micelles

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Z

BC

Solution ofmonomers Micellar

solution

Crystallinesuspension

CMT

A

Y

DX

CMC

Temperature

Concentrat ion of Detergent

Krafft point

Figure by MIT OCW.

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iii) EMULSIONS

Dispersions of one liquid in a continuous phase of

another liquid: O/W, W/O systems

The dispersed (discontinuous) phase consists of

microscopic droplets, usually 0.1-100 m in

diameters

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iv) SOLID CRYSTALS

Classically lipids such as Cholesterol (Gallstones,

Atheroma), fatty acids + bile acids (Enteroliths),

are pathologic

glycolipids (neural storage diseases) all

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Anhydrous Cholesterol and Cholesterol Monohydrate

Figures removed due to copyright reasons. Please see:

Shieh, H. S., et al. "Crystal structure of anhydrous cholesterol." Nature267 (1977): 287-9.

Craven, B. M. "Crystal structure of cholesterol monohydrate." Nature260 (1976): 727-9.

Figure 1 in Loomis, C. R., et al. "The phase behavior of hydrated cholesterol." J Lipid Res20 (1979): 525-535.

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Principal Mixed Lipid Systems in

Living Organisms

Stable Emulsions (dietary fat, plasma lipoproteins,

pre-digestion, etc.)

Mixed Micelles (bile, gut lumen, certain brainlipid storage diseases)

Mixed Liquid Crystals (biologic membranes,

serum lipoprotein X in cholestasis, myelin sheet,mixed vesicles in gut lumen, etc.)

intracellular fat droplets, gut luminal lipids

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BEHAVIOR OF LECITHIN IN WATER

Figure removed due to copyright reasons.

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ADDITION OF BILE SALT TO LECITHIN - CHOLESTEROL LIQUID CRYSTAL

Figure removed due to copyright reasons.

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Predictability Rule

Predominance Rule

Phase Rule (F=C-P+2)

The 3 P Rules

H Li id T Bi l i l

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How Lipids Traverse Biological

Membranes

As single molecules (molecule need not bewater soluble)

As aggregated particles (i.e., stable emulsions)

Transporter control: Genomic (slow),

nongenomic (fast)

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CELLULAR CHOLESTEROL HOMEOSTASIS

Lysosomal cholesterol

ester hydrolase

Free cholesterol

Increased Cholesterol Influx

ACAT

HMG CoA Reductase

LDL Receptor

CECE

CE CE

HDL

HMG CoAReductase

ACAT

Neutral

cholesterol

ester hydrolase

Cholesterolester

Acetate

LDL LDLreceptor

LDLreceptor

+_E RICH

Lipoprotein

LRP

HDLCell membrane

Liver Specific

Lipoprotein

Bile Salt

Bile

Figure by MIT OCW.

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100%

100%

20%Tissues

Liver Cel l

B/E Receptors

VLDL

IDL

LDL

1. All VLDL made in l iver.

2. ~ 80% of LDL removed by l iver.

The Liver And Plasma Lipid Hom eostasis

Figure by MIT OCW.

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CHEMICAL COMPOSITIONS OF HUMAN PLASMA LIPOPROTEINS

Figure by MIT OCW.

GI Movements of Single Molecules:

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GI Movements of Single Molecules:

Examples

Facilitators:

Biliary Secretion:

Nuclear Control:

Hepatic Uptake:

Binding:

Transport:

Enterocytes:

Same + hydrophobic sink in bileNeeds intact FIC1 function

ABCG5/ABCG8, (others

unknown)

BSEP, MRP2

SREBPs

LXR/RXR

FXR/RXR

SHP, LRH1

ApoB/E receptor

LRP receptor

NTCP 80%

OATPs 20%

ChE and free Ch in chylomicronsand nascent HDL

Albumen, HDL

LymphaticsPortal Blood

Proximal > Distal

Influx: NPC1L1Efflux: ABCG5/ABCG8

Distal Ileocytes

Influx: ASBT, FABP6,OAT/

Cholesterol/Phytosterols(insoluble)

Bile Salts(soluble)

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