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LECT 22: LIPIDS, MEMBRANES, AND CHOLESTEROL
Lipids and cholesterol in the body derive from food intake
and from de novo synthesis.
Phospholipids are principle constituent of cell membranes, and specialized
phospholipids participate in signal transduction pathways.
Lipid and cholesterol synthesis intermediate anchors serve to attach
certain proteins to membranes.
Cholesterol is a membrane constituent needed in all cells. Bile acids
used for intestinal fat uptake and nuclear hormones are synthesized
from cholesterol.
Cholesterol is only synthesized in the liver, so that all other tissues
must receive cholesterol by trafficking through blood in the form
of lipoprotein particles.
Phospholipids Have Glycerol Backbone, Two Fatty Acids, and Phosphate Alcohol
The Four Common Phospholipids
Phosphatidylinositol(PI) has diverse functions. In addition to being a major
membrane constituent, PI’s inositol ring can be phosphorylated to
generate a signal transduction intermediate. PI can also be further
modified to generate the GPI membrane anchor.
Phospholipid Synthesis Uses CDP Intermediates
Sphingosine Is a Fatty Amine Used to Generate the
Specialized Lipid Sphingomyelin
Fatty Acids Tend To Form Micelles, While Phospholipids Form
Bilayer Membranes That Are Water Impermeable
Fatty acids or other detergents can
solubize membranes,
dissolving them into mixed micelles
A Detergent’s “Strength” Reflects Types of Hydrophobic Interactions
It Can Disrupt
VERY WEAK DETERGENT: Disrupts only very weak hydrophobic
interactions. Example: Tween-20. Useful in protein binding reactions
(e.g., Western blot) to prevent nonspecific binding of antibody
to filter or filter-bound proteins.
MILD NONIONIC DETERGENT: Dissolves plasma membrane, other
non-nuclear membranes, and incorporates constituents into
detergent micelles. Examples: Triton X-100, Nonidet P40
STRONG IONIC DETERGENT: Solubilizes all membranes, disrupts
protein-protein interactions, and denatures proteins. E.g. SDS
Sonicated Phospholipid Forms Small Lipid Vesicles, Liposomes,
That Trap Aqueous Materials Inside
Lipophilic Protein Anchors Tether Proteins to Membranes
Some Proteins Contain Signal Motifs for Lipophilic Modification
Lipophilic anchor attachments accompanied by peptide cleavage
-C-A-A-X
-C
SH
S
Farnesylation (cytoplasmic)
C15
G-(6aa)-
M-G-(6aa)-
NH
Myristoylation (cytoplasmic)
C14
GPI
20aa
hydrophobic tail
GPI Anchoring (ER Lumen)
Membrane Fluidity Demonstrated By Photobleach Recovery
HMG-CoA Reductase Initiates the Cholesterol Synthetic Pathway
This reaction catalyzed by
HMG-CoA reductase
is rate-limiting for
cholesterol biosynthesis
Cholesterol Is Built From Six Isopentenes and C30 Cyclization
C5
Isopentyl
C10
Geranyl
C15
Farnesyl
C30
Squalene
Cholesterol Is The Precursor For Nuclear Hormones
Cholesterol Biosynthesis in Liver Regulated at the HMGCoAR Gene
HMGCoAR gene transcription controlled by transcription factor SREBP.
When cholesterol is abundant, its interaction with SCAP in the ER keeps
SREBP tethered to ER as part of larger precursor.
Decline in cholesterol allows SCAP/SREBP to move to Golgi, where
proteases liberate SREBP, which goes to nucleus to activated transcription.
Lipoprotein Particles Employ Specific Apolipoproteins to Package
Cholestero Estersl and Triglycerides in a Phospholipid/Cholesterol Shell
Lipoprotein Particles Are Taken Up By Cells By Specific Receptors
That Recognize the Apolipoprotein Component
After uptake, lysosomes degrade apolipoprotein, and cholesterols
are incorporated into endoplasmic reticular membrane
Lipids and Cholesterol Are Shuttled Through an Organ Network
EXCESS SERUM LDL INCREASES RISK OF CARDIOVASCULAR DISEASE
Genetic Causes of Cardiovascular Disease
Hypercholesterolemia cause by mutations in genes for LDLR or
LDL’s ApoB100, which prevent circulating LDL uptake
Mutations in ApoE cause reduction in HDL production, thereby
impairing circulating cholesterol trafficking back to liver
Clinical Management of Cardiovascular Disease or Risk
Dietary management, including restricting cholesterol and reducing
saturated fat and sugar intake
Cholesterol reuptake inhibitors: Cholestyramines taken orally bind
to bile acids in gut and prevent their reabsorption, thereby lowering
total cholesterol load
Statins (e.g., atorvistatin, lovastatin) inhibit HMG-CoA reductase,
thereby blocking de novo cholesterol synthesis in liver