Cholesterol Flashcards
Acetyl-CoA can lead to HMG-CoA which can lead to:
Ketone bodies
Cholesterol (then steroids)
What are some key features of cholesterol?
Rigid, hydrophobic, 4 rings
Enriched in plasma membranes of eukaryotes
Required for eukaryotic growth
Absent in prokaryotes
How is cholesterol important for membranes?
Modulates physical properties
Controls fluidity and curvature
Maintains integrity - prevents leaks
Cholesterol is a precursor to:
Bile salts (detergents- dietary fat absorption, more polar) Steroid hormones (androgens, estrogens, adrenal) Vitamin D3
How is cholesterol homeostasis maintained?
We lose the same amount of cholesterol (via bile salts and free cholesterol) each day as is made or ingested. (We make more than we eat)
How is cholesterol related to atherosclerosis?
Correlation
Narrowing and hardening of the arteries due to plaque - aggregate of cholesterol, fat, calcium, fibrin
Inflammatory
Many complicated biomolecules are made from ____________. List properties of these.
Isoprenoids (isoprene lipids) 5 C Steroids, cholesterol Essentail oils Natural antibiotics, antifungals Pheromones Carotenoids Drugs (taxol)
What is the basic process of isoprenoid biosynthesis to cholesterol?
C5 building block from acetyl-CoA (mevalonate pathway)
Joined to make a chain (Squalene)
Cyclization
Ring structures are decorated
What sources provide Acetyl-CoA for cholesterol biosynthesis?
Glycolysis, PDH
Fatty acid oxidation
Amino acid oxidation
Ethanol
________ is the branch point at the mevalonate pathway that determines that cholesterol will be made instead of ketones. This key regulatory step for cholesterol synthesis (dedicated pathway after this point).
HMG-CoA Reductase
Geranyl and faresyl are ________ precursors that are used to tether proteins to membrane.
Squalene
Storage and transport form of cholesterol
Cholesteryl ester
Water soluble transport lipids with phospholipid exterior, cholesterol and fatty acid interior, and proteins for regulation
Lipoproteins
Least dense (biggest, most fatty) lipoprotein. Moves dietary fat from GI to liver/body
Chylomicron
Moves fats (not just cholesterol) from liver to body
Very low density lipoprotein (VLDL)
Moves cholesterol from liver to body (other fats removed)
Low density lipoprotein (LDL)
Moves cholesterol from body to liver (smallest)
High density lipoprotein (HDL)
What is the typical cycle of LDL?
Exocytosed to membrane, LDL binds, endocytosis, LDL receptors recycled or degraded when directed by PCSK9
Familial hypercholesterolemia results from defects in ________ which causes LDL to stay in the blood.
LDL receptor
How do SREBPs regulate cholesterol metabolism?
SREBP = sterol regulatory element-binding protein (TF for LDL receptor)
SREBP/SCAP complex waits in ER with cholesterol in cell is high (low tc of LDLR and HMG-CoA reductase)
When cholesterol decreases, SCAP is released to allow SREBP to leave ER, cleaved by Golgi, ad into nucleus to bind DNA and active tc
How do statins lower cholesterol?
- ) 20-80mg dose partially blocks cholesterol syn in liver via HMG-CoA reductase (drug distribution ensures other peripheral tissues not affected)
- ) SREBP system in liver responds and increases tc of LDL receptor (senses low cholesterol in cell)
- ) Extra LDL receptors in liver allow more absorption of cholesterol from plasma
- ) New steady state is reached with lower circulating LDL
What are the beneficial effects of statins?
Cholesterol deposits in coronary arteries no longer expand
Significant lowering of second heart attacks
May prevent first heart attacks
Improvement in circulatory function
Reduction in mortality, fatal heart attacks, and other CV events (stroke, clots)
What are some adverse effects of statins?
Overall very safe
Myalgia (muscle pain) -harmless
Rhabdomyolysis (muscle break down) -rare but serious
Correlation with increased risk of Type 2 diabetes
How do PCSK9 inhibitors work?
PCSK9 directs LDL towards lysosomal degradation (more PCSK9 = less LDL = more blood cholesterol)
PCSK9 Ab lowers plasma cholesterol
-often with statin
-Ab so must be injected
