4.04 Cholesterol Synthesis Regulation Flashcards
What are the three main sources of cholesterol that enter the liver?
dietary - chylomicron remnants
extrahepatic - HDL
de novo - made in liver
What are the forms that cholesterol is excreted from the liver?
Secretion VLDL
Free cholesterol in bile
conversion to bile acids/salts
What is cholesterol important for in the body?
membrane components
plasma lipoproteins
bile acid, steroid, Vit D precursor
cholesterol structural components?
four fused rings
extremely hydrophobic
What form of cholesterol is stored within cells and even more hydrophobic?
esterified cholesterol
What makes cholesterol in the body?
nearly all tissues
(but especially liver, adrenal cortex, and reproductive)
Production of cholesterol begins with what?
acetyl coA (2)
Why do you need NADPH in cholesterol synthesis?
Used to reduce cholesterol and generate energy
cholesterol synthesis is responsive to what?
intracellular cholesterol concentration*
Where does cholesterol synthesis take place in a cell?
cytosol
Describe the key first two steps of cholesterol synthesis
(2) acetyl CoA -> acetoacetyl CoA
+ Acetyl CoA –> HMG CoA
Enz: ** HMG CoA Synthase**
Cholesterol synthesis mimics what other reaction within hepatocytes?
ketone synthesis
When does NADPH first come into play in cholesterol synthesis?
production of mevalonate from HMG CoA
Key regulating step (rate limiting) in cholesterol synthesis?
HMG CoA Reductase**
enzyme inhibited by cholesterol
needed to make mevalonate
NADPH required
What drug inhibits HMG COA reductase to lower cholesterol?
statins (inhibit endogenous production and promote more cell uptake from circulation)
Mutations in what gene cause Smith Lemli Opitz Syndrome?
DHCR7
needed for final step of cholesterol synthesis
AR disorder with a broad phenotypic spectrum including microcephaly, developmental delay, cardiac defects, syndactyly toes, etc. that leads to low cholesterol and accumulated precursors?
SLOS - Smith Lemli Opitz Syndrome
What enzyme catalyzes cholesterol storage within a cell?
ACAT acyl-CoA-cholesterol acyltransferase
What is the role of bile acids?
emulsify fats after a fatty meal and a way to excrete cholesterol (made more hydrophilic)
What can enhance the bile acid cholesterol excretion and lower endogenous cholesterol?
dietary fiber
exogenous cholesterol metabolism?
dietary cholesterol packed into chylomicrons
endogenous metabolism cholesterol?
lipids packed into VLDL in the liver
Reverse cholesterol pathway?
HDL transports cholesterol from extrahepatic tissue (plasma membranes) to the liver
What kind of plasma lipoprotein has the highest density of protein?
HDL
(protein > lipids)
What kind of plasma lipoprotein has the highest concentration of cholesterol?
LDL
What plasma lipoprotein has the highest concentration of TAG?
chylomicrons
Where are chylomicrons assembled to transport dietary lipids?
intestine
What kind of apolipoprotein do chylomicrons have?
ApoB-48
(first half = APOB gene)
What protein helps form teh chylomicron?
MTP microsomal triglyceride transfer protein
How do nascent chylomicrons integrate ApoE and ApoC-II to fully form?
HDL in circulation
Roles of ApoE and ApoC-II respectively?
ApoE = hepatocyte uptake of chylomicron remnant
ApoC-II = activate lipoprotein lipase
What protein hydrolyzes 90% of chylomicrons TAG into FA and glycerol in tissues?
lipoprotein lipase
VLDLs are generated where?
liver
Where does the free glycerol go?
liver for glycolysis
What kind of ApoB is in VLDL?
ApoB-100
VLDL is degraded in to what post LPL degrading teh TAG?
IDL
How can cholesterol ester be moved from HDL to VLDL?
via CETP (trade cholesterol ester for TAG)
What does IDL become?
LDL to be taken up by extrahepatic tissue and liver
What does ApoB-100 do?
help to stabilize LDL attachment to receptor in clathrin pit to be taken to by hepatocyte
Intracellular cholesterol inhibits HMG CoA reductase (endogenous metabolism) and the expression of what gene?
LDL receptor protein
(inhibit the uptake of cholesterol)
If not needed immeidtaley what esterifies the choelsterol?
ACAT
What kind of mutation is in Niemann Pick Type C? What is it responsible for?
NPC1 or NPC2
(transfer cholesterol out of lysosome into cytosol)
Where does the cholesterol accumulate in Neiman Pick Type C Syndrome?
lysosomes of liver, brain, spleem, and lung
What promotes the degradation of LDL receptors to increase the circulation of LDL?
PCSK9
What kind of mutation at PCSK9 is associated with reduced circulating LDL?
loss of function mutation
What kind of mutation at PCSK9 is associated with more circulating LDL?
gain of function mutation
HDL originates where?
liver and small inestine
What kind of Apo in HDL?
ApoA-1
What do HDLs do?
cholesterol from periphery to the liver
What catalyses teh esterification of cholesterol allowing them to be transported through circulation?
LCAT
What mediates the movement of cholesterol within a cell (inside to outside)?
ABCA1
What does HDL2 bind to on the liver to pass along the cholesterol (just expel the contents)?
SR-B1
What are the cholesterol scavengers to take excess cholesterol to the liver?
HDL
What activates LCAT?
ApoA-I
What interacts with the mature HDLs to pass along HDL from intracellular to them?
ABCG1
What conditions result in low HDL levels or almost undetectable levels? What mutation?
Familial HDL Deficiency
Tangier Disease
Mutations to ABCA1
(Can’t take up cholesterol)
What catalyzes the catabolism of cholesterol to bile acids?
CYP7A1
Where are 95% of the bile acids secreted by the intestine reabsorbed?
terminal ileum
What is enterohepatic circulation?
continuous cycle of bile acid secretion and excretion
What is teh most common bile acid?
cholate (water soluble)
About how much bile acids are excreted and how?
<3% feces
some excess cholesterol too
What are bile acid-binding resins?
increase bile acid secretion to reduce overall cholesterol (by binding with high affinity and insoluble so can’t be reabsorbed)
What to note about using bile acid resins clinically?
patient would need to consume large amounts so used in conjunction with other therapies
What regulated cholesterol production overall?
intracellular cholesterol
ATP supply
glucagon + insulin
What makes HMG-CoA reductase inactive?
phosphorylation by AMPK
What does glucagon do (cholesterol synthesis)?
promotes the inactive form of HMG-CoA reductase, especially in fasting states
What does insulin do (cholesterol synthesis)?
promote the ACTIVE form of HMG-CoA reductase
What do oxysterols do?
also inhibit HMG-CoA reductase by indicating a lot of esterified cholesterol (storage)
How can you regulate cholesterol long-term?
via SREBPs
held in ER with SCAP –> insig (sterol sensors)
If there is low cholesterol in the cell how does that influence the expression of the LDL gene?
want to promote LDLR expression
(via Insig being ubiquitinated - SCRAP-SREBP cleaved at Golgi -
SREBPs domain activated transcription at the nucleus)
Statins do what to lower cholesterol levels?
inhibit De novo - endogenous
lower plasma LDL
indirectly simulate LDLR
If statins do not work what else can you use (pharm)?
Ezetimibe
blocks NPC1L1 (cholesterol absorption in the intestine)
What does Ezetimbie block?
cholesterol absorption in the intestine via NPC1L1
