lect 22: lipids, membranes, and cholesterol
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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. - PowerPoint PPT PresentationTRANSCRIPT
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 FormBilayer Membranes That Are Water Impermeable
Fatty acids or other detergents cansolubize membranes,
dissolving them into mixed micelles
A Detergent’s “Strength” Reflects Types of Hydrophobic InteractionsIt 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
SH
-C
S
C15Farnesylation (cytoplasmic)
M-G-(6aa)- G-(6aa)-
NH
C14Myristoylation (cytoplasmic)
GPI Anchoring (ER Lumen)
20aahydrophobic tail
GPI
Membrane Fluidity Demonstrated By Photobleach Recovery
This reaction catalyzed byHMG-CoA reductase
is rate-limiting forcholesterol biosynthesis
HMG-CoA Reductase Initiates the Cholesterol Synthetic Pathway
C5
C10
C15
C30
Geranyl
Isopentyl
Farnesyl
Squalene
Cholesterol Is Built From Six Isopentenes and C30 Cyclization
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 PackageCholestero Estersl and Triglycerides in a Phospholipid/Cholesterol Shell
Lipoprotein Particles Are Taken Up By Cells By Specific ReceptorsThat 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