Lysosomal Accumulation of Lipids Flashcards
what is the major cholesterol carrier in the blood?
LDL
describe cellular uptake of cholesterol
LDL binds to LDLR on the membrane and the LDL complex moves to coated pits on the membrane which invaginates and forms a coated vesicle, the vesicle eventually fuses with a lysosome, where degraditive enzymes release the FAs and cholesterols
what does the lipoprotein apo-100 become?
it gets digested to become amino acids
where dose cholesterol go after being liberated by the lysosome?
It goes one of two places: 1) goes to the plasma membrane to fill membrane synthesis needs or 2) goes to the ER to be re-esterified by ACAT
what is ACAT?
There are two isozymes of ACAT:
ACAT1 is the predominant form in non-heptaic cells, the cholesterol esters form droplets for storage
in hepatic cells, they form neutral lipid cores of LDL
what is the cause of Niemann pick type C disease?
unesterified cholesterol, phospholipids, sphingomyelin and glycolipids (especially GM2 ganglioside) accumulate in lysosomes of various organs, especially liver and spleen mutations which occur in either NPC1 or NPC2
NPC1 transmembrane protein in lysosomes that binds to cholesterol with high affinity results in delayed homeostatic response to LDL-bound cholesterol
what is filipin?
fluorescent stain capable of detecting cholesterol accumulation in fibroblasts used as a diagnostic for NPC
what are the 3 major cholesterol pools in cell?
1) LDL, 2) de novo synthesis 3) cholesterol/cholesterol ester cycle
how are NPA and NPB different from NPC?
A and B, the lesion is at the lysosomal sphingomyelinase, causing an accumulation of sphingomyelin in the lysosome
C the defects are in NPC1 or 2 and the accumulation of sphingomyelin and glycolipids is secondary
what are gangliosides?
acidic glycolipids that are concentrated in the outer leaflets of plasma membranes that are important for signal transduction
what is the structure of ceramide and sphingomyelin?
a central moiety in sphingolipids, a sphingolipids amino group is acetylated to form ceramide-the hydroxyl group of ceramide can be substituted with various groups to form different compounds
when substituted with phosphorylcholine, it becomes sphingomyelin, with acidic oligosaccharide, it becomes a ganglioside, and with glucose/galactose it becomes cerebroside
where does the construction of gangliosides occur?
ER and Golgi
glycosphingolipids are important for what purpose?
glycosphingolipids are important plasma membrane signalers and there is constant turnover, if a hydrolase is damaged in the pathway, there can be severe deficits that occur due to the build up of lipids especially in neres
what is Tay-Sachs disease?
mutations in the hexokinase A enzyme that are responsible for lysosomal breakdown of gangliosides which causes a buildup of GM2 gangliosides, normally these gangliosides are turned over at a high rate in CNS of young children the diagnosis occurs via a hexokinase A assay
Clinically, there can be severe mental retardation, progressive weakness, cherry red retina and death by age 2
