L22 Cholesterol Flashcards
Hyper-chylomicronemia can be caused by… (select all that apply)
A. apoA-I deficiency
B. ApoE deficiency
C. Lipoprotein lipase deficiency
D. ABCA1 mutations
E. ApoC-III mutations
C, E since they would result in NO chylomicron breakdown
B would result in increased chylomicron remnants since they will not be taken up by the liver
A, D concern HDL, not chylomicrons
Abnormally high [LDL] in plasma can be caused by loss of function of… (select all that apply)
A. Lipoprotein lipase
B. LDL-R
C. ApoB-100
D. Pancreatic lipase
E. ABCA1
B, C since without either LDL-R or ApoB-100, LDL cannot be taken up by the liver or peripheral tissues
E is related to HCL not LDL
D is in the GIT so there’s no effect
A is related to chylomicrons
Low HDL concentrations may result from mutations in… (select all that apply)
A. LDL-R
B. lipoprotein lipase
C. LCAT
D. ABCA1
E. apoA-I
C, D, E: LCAT is needed for HDL maturation (pre-HDL -> HDL), ABCA1 and apoA-I are needed for HDL precursor (pre-HDL)
What does ABCA1 do?
It is a floppase that transport cholesterol from the inner leaflet to the outer leaflet so that it can interact with apoA-I (and pre-HDL)
What does LCAT do?
It turns pre-HDL into HDL (maturation)
What does CETP do?
It transports cholesterol ( cholesteryl ester) from HDL into VLDL and TAG from VLDL into HDL
What happens if SRB1 is non-functional?
HDL cargo cannot be transferred to the liver
What happens if you have LDLR-deficiency?
Too much LDL -> high CVD risk
What happens if you have ABCA-1 deficiency?
Too little HDL -> high CVD risk
What is good and bad cholesterol?
There is no good or bad cholesterol: too much LDL or too little HDL both cause high CVD risk
HDL vs LDL: what do they do?
HDL removes excess cholesterol
LDL carries cholesterol to cells
Where does NADPH come from?
PPP cycle
TF: cholesterol synthesis requires NADH
F, it requires NADPH
TF: cholesterol can be synthesized by isoprenoids
True
What is the key regulatory enzyme in cholesterol synthesis and what does it produce?
HMG-CoA reductase, mevalonate
TF: cholesterol can be synthesized from acetyl-CoA
True
How much ATP and NADPH is required for the synthesis of 1 cholesterol molecule in the mevalonate pathway
36 ATP and 16 NADPH
What is farnesyl pyrophosphate?
It is a cholesterol precursor (right before squalene) that acts as a lipid anchor meaning it anchors the protein to the membrane (non-raft)
What are the 2 ways cholesterol is regulated through homeostasis?
Body: diet + synthesis vs excretion
Cell: uptake from circulation vs efflux from cell
LDLR vs ABCA1: which one is involved in uptake of cholesterol and which one is involved in efflux of cholesterol?
LDLR = uptake: cholesterol from LDL is absorbed into cell
ABCA1 = efflux: cholesterol is transformed into preHDL (then to HDL)
What is cholesterol excreted as?
Build acids and biliary cholesterol
What are the 2 ways to regulate cholesterol synthesis via HMG-CoA reductase?
- Energy state
- Gene regulation ‘ sensing [cholesterol]
What is the melavonate pathway
It is the pathway for cholesterol and other isoprenoid synthesis (aka HMG-CoA reductase pathway or isoprenoid pathway)
In what state is HMG-CoA reductase in when high [AMG]/[ATP]
High [amg/atp] describes a low energy state. The lack of atp means cholesterol synthesis cannot occur so hmg-coa reductase is off/inactive and phosphorylated
What does AMPK do?
It phosphorylates hmg-coa reductase to turn it off
How is cholesterol synthesis regulated through gene regulation?
High intracellular cholesterol makes it so that insig stays bound to Scap thus inhibiting Scap-SREBP transport to golgi
Low intracellular cholesterol allows Scap-SREBP transport to golgi, where the SREBP (transcription factor) is cleaved by S1P and S2P. Then, SREBP can activate SRE (sterol-response element) found in promoter to increase hmg-coa reductase and LDL-R synthesis increasing cholesterol synthesis and LDL uptake respectively (increasing cholesterol uptake)
How can cholesterol synthesis be pharmacologically regulated?
A. Hmg-coa synthase inhibitor
B. Hmg-coa synthase activator
C. Hmg-coa reductase inhibitor
D. Hmg-coa reductase activator
C, hmg-coa reductase inhibitor (aka statins)
What would high levels of SREBP in the nucleus indicate about cholesterol levels?
It would indicate low cholesterol levels
What is the function of cholesteryl esters?
- Intestine, liver, adipocyte
- Inside cells
- Plasma
- Chylomicrons (intestine), VLDL (liver), lipid vesicles (Adipocyte)
- GPAT - Lipid droplets, VLDL (inside cells)
- ACAT transfers the cholesterol into the cells by turning it into cholesteryl ester - HDL (plasma)
- LCAT
What are the 4 sterol derivatives
Cholesteryl ester
Bile salts
Hormones
Vitamin D
What is the function of VLDL
Delivering TG to adipocytes and become LDL
What is the function of LDL
Supply various organs with cholesteryl ester
To what organs does HDL deliver cholesterol to and what happens to the cholesterol?
Liver -> bile acids
Adrenal glands -> steroid hormones
Skin -> vitamin D
Which organ is the central hub for cholesterol metabolism and why?
Liver, it produces cholesterol for other organs via LDL
How is hmg-coa reductase regulated (by which substrates)
AMP/ATP ratio and [cholesterol]
What does statin do
It inhibits hmg-coa reductase and deceases [LDL]
