hst.121: gastroenterology, fall 2005 lipids › courses › health-sciences-and... · -nh, -c=o,...
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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 withaliphatic chains of at least 12C atoms and/oraromatic/aliphatic structures with at least 3 ringswhich may be fused
• Old system of classification based on solubility inorganic 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 Basedon 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 Soc 45 (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 of soluble 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
B C
Solution of monomers Micellar
solution
Crystallinesuspension
CMT
A
Y
DX CMC
Tem
pera
ture
Concentrat ion of Detergent
Krafft point
Figure by MIT OCW.
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Self-Aggregated States
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 µm in diameters
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Self-Aggregated States
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." Nature 267 (1977): 287-9.
Craven, B. M. "Crystal structure of cholesterol monohydrate." Nature 260 (1976): 727-9.
Figure 1 in Loomis, C. R., et al. "The phase behavior of hydrated cholesterol." J Lipid Res 20 (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 brain
lipid 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
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How Lipids Traverse Biological Membranes
• As single molecules (molecule need not be water soluble)
• As aggregated particles (i.e., stable emulsions) • Transporter control: Genomic (slow),
nongenomic (fast)
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CELLULAR CHOLESTEROL HOMEOSTASIS
Lysosomal cholesterol ester hydr olase
Free cholesterol
Increased Cholesterol Influx
ACAT
HMG CoA Reductase
LDL Receptor
CECE
CE CE
HDL
HMG CoAReductase
ACAT Neutral cholesterol ester hydrolase
Cholesterol ester
Acetate
LDL LDL
receptor
LDL receptor
+_ 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 Homeostasis
Figure by MIT OCW.
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CHEMICAL COMPOSITIONS OF HUMAN PLASMA LIPOPROTEINS
Figure by MIT OCW.
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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
SREBP’sLXR/RXR
FXR/RXRSHP, LRH1
ApoB/E receptorLRP receptor
NTCP – 80%OATPs – 20%
ChE and free Ch in chylomicrons and nascent HDL
Albumen, HDLLymphaticsPortal Blood
Proximal > DistalInflux: NPC1L1Efflux: ABCG5/ABCG8
Distal Ileocytes Influx: ASBT, FABP6, OATα/β
Cholesterol/Phytosterols(insoluble)
Bile Salts(soluble)
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That’s All Folks!