Lysosomal Accumulation of Lipids Flashcards
what is the major cholesterol carrier in the blood?
low density lipoprotein (LDL)
describe cellular uptake of cholesterol
LDL binds to LDL receptors on the membrane. the LDL complex moves to coated pits on the membrane, which invaginates and forming a coated vesicle. the vescile eventually fuses with a lysosome, where degraditve enzymes release the fatty acids and cholesterols
what does the lipoprotein apo-100 become?
digested to become amino acids
where does cholesterol go after being liberated in the lysosome?
one of 2 places
- goes to the plasma membrane to fill membrane synthesis needs
OR
- ER to be re-esterified by ACAT. there are 2 isozymes of ACAT, with ACAT1 being the predominant form. in non-hepatic cells, the cholesterol esters form droplets for storage. in hepatic cells, they form the neutral lipid cores of LDL.
what is the cause of Niemann pick type C?
unesterified cholesterol, phospholipids, sphingomyelin, and glycolipids (especially GM2 ganglioside) accumulate in lysosomes of various organs, especially liver and spleen
mutations occur in either NPC1 or NPC2
NPC1- transmembrane protein in lysosomes that binds to cholesterol w/ high affinity
NPC2- soluble protein in lysosomes that binds to cholesterol w/ high affinity
results in delayed homeostatic response to LDL-bound cholesterol
filipin
flourescent stain capable of detecting cholesterol accumulation in fibroblasts. used as a diagnostic test in NPC cases
what are the 3 major cholesterol pools in cells?
- from LDL
- de novo synthesis
- cholesterol/cholesterol ester cycle
how are NPA and NPB different from NPC
in A and B, the lesion is at lysosomal sphingmyelinase, causing an accumulation of sphingomyelin in the lysosome.
in C, the defects are in NPC1 or 2, and the accumulation of sphingomyelin and glycolipids is secondary
gangliosides
acidic glycolipids concentrated in the outer leaflets of plasma membranes what are important for signal transduction
ceramide and sphingomyeline structure
a central moiety in sphingolipids. a spingolipid’s amino group is acetylated to form ceramide.
the hydroxyl group of ceramide can be substituted w/ various groups to form different compounds. for example, when substituted w/ phosphorylcholine, it becomes sphingomyeline.
subbed w/ an acidic oligosaccharide, becomes a ganglioside
subbed w/ glucose or galactose, becomes a cerebroside
where does the construction of gangliosides occur?
ER and golgi
glycosphingolipids are important PM signalers, and there is constant turnover. if a hydrolase is damaged in the pathway, severe deficits occur d/t buildup of lipids, especially in nerve
ok
describe Tay Saches disease
mutations in Hex A enzyme responsible for lysosomal breakdown of gangliosides causes a buildup of GM2 gangliosides. normally gangliosides are turned over at a high rate in CNS of young children
diagnosis via Hex A assay
prognosis- severe retardation, progressive weakness, cherry red retina, death by age 2
