Cholesterol Flashcards
Bile Salts
detergents that facilitate dietary lipid absorption in the intestines (large amount required)
Cholesterol is a precursor to what molecules?
Bile Salts, steroid hormones (andro/estro) (adrenal), vitamin D3
Total Body cholesterol amount?
~50g
T or F: We make more cholesterol than we ingest from diet?
TRUE
Atherosclerosis
narrowing and hardening of arteries due to plaque (aggregate of cholesterol, fat, calcium, fibrin)
T or F: people with higher cholesterol concentration have higher chance of atherosclerosis?
TRUE
How is cholesterol synthesized in the body?
- two Acetyl CoA are combined to produce HMG-CoA
- HMG-CoA reductase converts HMG-CoA to mevalonate (KEY REGULATORY STEP - STATINS AND BIOLOGICALLY)
- Mevalonate is converted to 5-C isoprene building blocks
- Isoprene building blocks are combined to get a long chain (squalene)
- Squalene is cyclized to get ring structure, then decorated and adorned for final cholesterol structure
What is the key regulatory point in Cholesterol synthesis?
HMG-CoA reductase
How is cholesterol transported in the body?
Must be packaged - cholesterol esterification (storage form)
What are the lipoproteins that transport cholesterol?
- chylomicron - least dense; moves dietary fat from GI to liver/body
- VLDL - moves fats from liver to body
- LDL - VLDL after removal of fat; only cholesterol left; moves cholesterol from liver to body
- HDL - cholesterol from body to liver
LDL
low density lipoprotein; VLDL after removal of fat; only cholesterol left; moves cholesterol from liver to body; correlation of more LDL makes it more likely to have heart disease;
LDL receptor sequence
receptor on surface, when binds it is endocytose; lysosome fuses with endosome and hydrolyzes the content; receives AA, FA, and cholesterol for absorption; LDL receptor gets recycled back onto surface
HDL
high density lipoprotein; cholesterol from body to liver; correlation of more HDL makes it less likely to have heart disease
Familial Hypercholesterolemia
autosomal codominant; extremely high cholesterol; “tendon xanthomas - hallmark sign of biochem dysfunctions; homozygote = high LDL; heterozygote = half as high; LDL receptor is broken, LDL not taken up from blood
Sterol Regulatory element-binding proteins (SREBPs)
transcription factor that binds to SRE to promote transcription of LDL and HMG-CoA reductase
SREBP/SCAP Complex w/ high cholesterol
SCAP in the ER detects when cholesterol inside the cell is high and binds to SREBP, holding it in the ER and preventing expression of the LDL receptor and HMG-CoA reductase
SREBP/SCAP Complex w/ low cholesterol
SCAP releases SREBP, which moves to the Golgi and is cleaved, freeing the transcription factor. Leads to expression of LDL receptor and HMG-CoA reductase
Statins
inhibitors of HMG-CoA reductase; block synthesis of cholesterol;
Statin mechanism of action
taken up by liver and partially blocks cholesterol synthesis there (does not affect peripheral tissue); SREBP system in liver increases transcription of LDL receptor; extra LDL receptors allow more absorption of cholesterol from plasma; 35-45% decrease in LDL
Statin Effects
cholesterol deposits in coronary arteries no longer expand; lowering of second heart attacks in patients with heart disease; may prevent first heart attacks in pts w/ high cholesterol; improvement in circulatory system
Statins Adverse Effects
Muscle pain, risk of TIIDM
PCSK9
Bind to LDL receptors and directs them towards degradation
PCSK9 Inhibitors
inhibit PCSK9 = increased LDL receptors = lower blood cholesterol; available therapeutic - 40-70% reduction of LDL w/ statins
