Plasmalogen & Lipid Signaling Flashcards
How do plasmalogen levels relate to Alzheimer Disease?
Low levels of plasmalogen correlated with severe Alzheimer Disease.
Plasmalogen is an abundant phospholipid, particularly in the CNS and brain so deterioration of brain tissues lowers body and serum plasmalogen
How is plasmalogen synthesized?
Completed in the peroxisome. Synthesized from DHAP
- Fatty acid transferred to C1 of dihydroxyacetone P molecule (DHAP)
- Fatty acid exchanged with fatty alcohol before another fatty acid is added to the C2 position of DHAP
- Polar head group added to C3 position
Describe the structure of plasmalogen
Contains a fatty alcohol in an ether linkage at carbon 1 of glycerol backbone
What is a peroxisomal biogenesis disorder and what do patients present with?
Zellweger Syndrome.
Pt will have low amount of plasmalogens in plasma membranes
How does a patient present with a Sphingolipid Degradation Disorder?
Called Sphingolipidoses.
Accumulation of sphingolipid degradation products in lysosomes, particularly in phagocytotic cells like white blood cells.
Membranous structures form within lysosomes
Gaucher Disease
Sphingolipidosis (lysosome storage disease)
Rare autosomal recessive disorder that presents with splenomegaly, intellectual disability, and erosion of long bones. Also liver and spleen enlargement
Caused by insufficent beta-glucosidase activity leader to accumulation of glucocerebroside in lysosomes
Pt will have undegraded sphingolipids in macrophages and low glucocerebrosidase activity
What are sphingolipids? What is their structure and function?
Large and diverse family of membrane lipids not derived from glycerol
Have a carbohydrate head group
Create a carbohydrate layer on outside of the plasma membrane for protection and surface recognition
Synthesis begins with bond formation between serine and fatty acid.
Describe the synthesis of Sphingolipids
Begins at endoplasmic reticulum and continues in Golgi apparatus
- Transfer of activated fatty acid to the carboxyl group of serine producing dihydrosphingosine
- Transfer of fatty acid to amino group of serine backbone forming dihydroceramide
- Polar head groups added to ceramide
What polar head groups added to ceramide create what sphingolipids?
- Transfer of choline -> Sphingomyelin
- Transfer of glucose/galactose -> Gluco or Galactocerebroside
- Addition of sulfated sugar -> Sulfatide
- Addition of neutral oligosaccharides -> Globoside
- Addition of negatively charged oligosaccharides -> Ganglioside
What is required for sphingolipid degradation?
Each of the bonds in sphingolipid requires a specific enzyme for degradation
If bond cannot be broken - lipid accumulates in lysosome and you get sphingolipidosis
How do patients present with lysosomal storage disease?
Congenital, progressive, recessive disorders.
Generally involve the spleen (lysosome-rich)
Sphingolipidoses - Accumulation of lipids and often involving the brain
Mucopolysaccharidoses - accumulation of acidic carbohydrates (GAG)
Less common is Pompe - Accumulation of glycogen
Disorder of general lysosomal function - I-cell disease
What is the function of phospholipases?
Phospholipases cleave phospholipids and initiate lipid signaling
Functions:
- Degradation in gfeneral
- Lipid remodeling - removal of one FA to prepare for attachment of another
- Signaling - release of lipids and head groups from membrane
What do phospholipases PLA1, PLA2, and PLC?
PLA1 and PLA2 cleave fatty acid from glycerol backbone
PLC removes phospho-head group
Arachidonic Acid in Membranes
Arachidonic acid is precursor for lipid signaling (e.g. in inflammation)
Synthesized from essential FA linoleic acid
Inserted into inner leaflet of plasma membrane through FA exchange
How is arachidonic acid inserted into the inner leaflet of the plasma membrane?
- Phospholipase A2 removes a fatty acid from a membrane lipid
- Acyltransferase adds arachidonic acid and replaces where fatty acid was
