Cholesterol Metabolism (Exam 2, Lipid Lecture 2) Flashcards
Where is VLDL synthesized?
In the liver and is secreted as nascent with apo B-100
What does VLDL contain?
Endogenous TAG
It does NOT carry dietary lipids
How does VLDL become mature?
In blood, HDL will transfer apo C-II and apo-E, so now VLDL can interact with peripheral tissues
What protein is required for LPL activation?
Apo C-II
What happens once TAG is transferred to the peripheral tissues?
In the blood, some of the remaining TAG molecules are going to be transferred from VLDL to HDL. HDL will then head back to the liver.
Some of the cholesterol esters from HDL are then going to be transferred over to VLDL. This is accomplished by an enzyme called CETP.
How are cholesterol esters from HDL going to be transferred over to VLDL?
Via CEPT enzyme
What happens once the TAG molecules have been transferred from VLDL to HDL?
The apo C-II and apo-E proteins are also returned to HDL
Apo B-100 remains on VLDL
This equates to the brief phase of IDL (intermediate-density lipoprotein)
IDL
Intermediate-density lipoprotein
Once the TAG, apo C-II and apo-E proteins are all returned to HDL
The liver can take up IDL via apo-E protein; however, most of the VLDL that is in circulation at this point is going to be used to form LDL. Remember LDL has a high concentration of cholesterol, not a whole lot of TAG molecules remain at this point.
LDL
Low density lipoprotein
Contains: high concentration of cholesterol
Function: Delivery cholesterol to peripheral tissues, OR return it to the liver
70% of the cholesterol in the plasma is found in LDL
What is the fate of cholesterol once it is inside the cell?
Within the lysosome, ACYL COA:CHOLESTEROL ACYL TRANSFERASE (ACAT) transfers FAs to cholesterol to form cholesterol esters for storage and potentially 3 other functions
What are cholesterol esters used for within the lysosome?
- Within the cell membrane phospholipid bilayer
- Major precursor for synthesis of steroid hormones
- Major precursor for the synthesis of bile acids
or storage, as well
If cholesterol esters are being stored within the lysosome, what 3 important mechanisms occur?**
- Inhibition of expression of HMG CoA reductase resulting in reduced synthesis of cholesterol
- Degradation of HMG CoA reductase
- Reduced expression and synthesis of LDL receptor
(TRUE/FALSE)
The cell can make cholesterol itself.
TRUE
What is a clathrin-coated vesicle?
When the LDL particle is endocytosed and brought into the cell.
Where is HDL cholesterol formed?
The mature form will form in the blood
Lipid + apo A-1 secreted from the liver and intestines
HDL is poorly understood
What is the function of HDL?
Serves as a circulating reservoir for Apo C-II and Apo-E, which it transfers over to the chylomicron and VLDL
Nascent HDL functions to uptake cholesterol from peripheral tissues and transport it to liver = “good cholesterol reputation.”
LCAT
Lecithen:choleterol acyltransferase (LCAT)
Synthesized and secreted by the liver, binds to HDL and facilitates the uptake of cholesterol in the blood from peripheral tissues.
Aka- helps HDL take up peripheral cholesterol
CETP
Cholester ester transfer protein (CETP)
Facilitates the transfer of cholesterol from HDL to VLDL during HDL metabolism.
This allows HDL2 to scavenge up more cholesterol from peripheral tissues on its way to the liver.
What happens when HDL returns to the liver?
HDL returns to the liver and cholesterol is used for bile acid synthesis
HMG CoA reductase
the rate limiting step in cholesterol synthesis within the cytoplasm
Where can cholesterol be synthesized?
In most tissues:
Liver
Intestines
Adrenal cortex
Reproductive tissues
Where do the carbons for cholesterol synthesis come from?
Acetyl-CoA
Cholesterol is made from acetyl-CoA fragments
What is the initial step in cholesterol synthesis?
2 acetyl-CoA molecules come together to form ACETOACETYL-COA via THIOLASE (cytoplasmic).
What is the main reducing agent in cholesterol synthesis?
NADPH
What is the second step in cholesterol synthesis?
ACETOACETYL-COA combines with another acetyl-CoA to form HMG-CoA via HMG CoA synthase.
What is the third step in cholesterol synthesis?
HMG-CoA will be reduced via HMG-CoA reductase w/ 2 NADPHs, forming MEVALONATE
How is HMG-CoA reductase regulated?
- Gene expression
- Degradation
- Covalent modulation
Explain gene expression regulation of HMG-CoA reductase.
++ Insulin (increases the production of the enzyme)
— Glucagon (decreases production)
Explain degradation regulation of HMG-CoA reductase.
High cholesterol will cause HMG-CoA reductase to bind proteins and tag itself for degradation by proteasome
Storage of cholesterol can signal to degrade the enzyme because the cell does not need to make any more cholesterol, if it is being taken into the liver.
Explain covalent modulation regulation of HMG-CoA reductase.
ACTIVE = UNPHOS via PROTEIN PHOSPHATASE
INACTIVE = PHOSHORYLATED via AMPK (activated by AMP aka low energy in the cell)
Which enzyme is targeted in statin medications?
HMG-CoA reductase enzyme as the statin works to inhibit this enzyme and prevents the body from making cholesterol.
How is LDL formed?
VLDL –> IDL –> LDL
