Cholesterol Flashcards
How many carbon atoms compose cholesterol?
27 carbon atoms
What is the structure of cholesterol?
27 carbon atoms, consists of cyclic rings with a hydrophobic tail steroid ring
Carbon and hydrogen,
C3 hydroxyl group
Why is cholesterol important?
Fluid dynamics within phospholipid bilayer, enables mechanical stability & fluidity
How does cholesterol maintain fluid stability within the phospholipid bilayer?
The cholesterol ring system interferes with motions of the fatty acid side chains
What is the first step of cholesterol synthesis?
Isopentenyl pyrophosphate- activated isoprene synthesis
What is the second stage of cholesterol synthesis?
Condensation of 6 molecules of isopentenyl pyrophosphate to form squalene (cytoplasmic reactions)
What is the fate of squalene?
Squalene undergoes demethylation and cyclisation to give cholesterol by monooxygenases
How is isopententyl pp formed (stage 1 &2)?
Two molecules of acetyl-CoA condense to form four carbon acetyoacyl-CoA
This is added to acetyl-CoA
Forms 3-hydroxy-3-methyl-glutaryl-CoA (HMG-CoA)
Converted into isopentenyl
What happens to HMG-CoA?
HMG-CoA reductase reduces HMG-CoA into Mevalonate
Which molecule provides the reducing power for the reduction of HMG-CoA into Mevalonate?
NADP+
Where does reduction HMG-CoA occur within a cell?
Within the cytoplasm
What is the fate of mevalonate?
Undergoes sequential phosphorylation at hydroxyl groups attached to c3 and c5 by kinase; decarboxylated into Isopenenyl-PP
What molecule is consumed for the phosphorylation of mevalonate?
ATP
What is the first step of squalene formation after isopentyl-PP is formed?
2 molecules of isopentenyl-PP condense to form dimethylallyl-pp
What happens to dimethylallyl-pp?
Addition of isopentenyl to form 15 carbon species
What enzyme catalyses the farnesyl-pp reaction?
Geranyl transferase
What is the term for the 15 carbon compound formed from 3 isopentenyl-pp?
Farnesylpp
How is squalene formed?
2 molecules of Farnesyl-pp condense, by squalene synthetase
Where does demethylation and cyclisation of squalene occur?
Endoplasmic reticulum
What is the fate of squalene?
Reduced in the presence of oxygen and NADPH, forms squalene epoxide
How is cholesterol formed from squalene?
Squalene –> squalene epoxide –> lanosterol –> cholesterol
What does cholesterol decompose into?
Glycocholate, taurocholate
What are steroid hormones derived from?
Cholesterol
What 5 classes of steroid hormones derive from cholesterol?
Oestrogens Androgens Corticosteroids Mineralcorticoids Progesterones
What is the role of cholesterol in vitamin-D synthesis?
7-dehydrodcholesterol within epidermis –> provitamin-d3 –> Vitamin-d3 –> calcitriol
What is familial hypercholesteroaemia?
Monogenic dominant trait, cholesterol transportation is defective
What type of mutation is FH?
Loss of function in the LDL-receptor gene
How can FH be controlled?
Inhibition of de no cholesterol synthesis in the liver
Reduction of dietary cholesterol absorption
What drug can reduce cholesterol synthesis?
HMG-CoA-Reductase inhibitors (Statins)
Resins(Sequestration of bile acid complexes)
What is lovastatin?
Statins are a competitive inhibitor of HMG-CoA reductase, resembles 3-HMG, thus mevalonate cannot be synthesised
What are resins (cholestryamine) ?
Bind or sequester bile-acid cholesterol complexes, prevents their reabsorption by the intestine
Orlistat function?
Inhibition of pancreatic and gastric lipases
How do chylomicrons enter the bloodstream?
Lacteals of the intestine to the thoracic duct and to the left subclavian vein where they enter the bloodstream
How are chylomicrons incorporated into tissues?
Lipoprotein lipase
What are the 3 major steps of cholesterol synthesis?
- Synthesis of isopentenyl pyrophosphate, an activated isoprene unit which serves as a key building block (cytoplasm).
- Condensation of six molecules of isopentenyl pyrophosphate to form squalene (cytoplasm).
- Cyclisation and demethylation of squalene by monooxygenases to give cholsterol (ER).
How is cholesterol transported in LPs?
As cholesterol esters
Life cycle of VLDLs, LDLs, IDLs and HDLs
How do serum cholesterol levels vary with different types of FH?
Heterozygous: 2-3x - Atherosclerosis in mid age
Homozygous: 5x - Atherosclerosis in adolescence
How is LDL endocytosed?
- Binding to LDLR
- Endocytosis
- Clathrin coat is uncloated
- Fusion with endosome
- Transfer to lysosome
- Budding off to transport vesicles
- Return of LDL to membrane+exocytosis
What is HMG CoA inhibited by?
Statins, mevalonate, cholesterol, bile salts
What are the 5 major classes of FH?
What is the purpose of LCAT?
Creating cholesterol esters
