2. Introduction to Lipids and Lipoprotein Metabolism (Part II) Flashcards
What is the transfer of cholesterol from cell membranes of peripheral cells to HDL driven by?
By the higher concentration of UC on peripheral cells
What are the requirements for the synthesis of HDL?
- Apo A-1, made by hepatocytes, requires phosphatidylcholine
- Apo A-1 is associated with CM. As TG decreases, then the phospholipids and Apo-A1 pinch off and become HDL
What are the effects of FH cells in response to lipoprotein addition?
- No effects on CE stores
- No effect on rate of UC synthesis
- No effect on HMG-CoA reductase activity
What are your tracing with radioactive iodine125?
Allows us to follow the protein portion of a lipoprotein
What are you tracing with radioactive hydrogen3?
- Fatty acyl chains
- Cholesterol moiety
What are doubly labeled lipoproteins?
Labeled with radioactive tracers on the protein and on the lipid
What is the dysfunction of FH cells?
FH cells are unable to bind, internalize, or metabolize LDL
What are the effects of increasing LDL concentration in normal cells during binding, internalization, and hydrolysis?
- Binding: increase with concentration
- Internalization: increase with concentration
- Hydrolysis: increase with concentration
What are the effects of increasing LDL concentration in FH cells during binding, internalization, and hydrolysis?
- Binding: no increase with concentration
- Internalization: slight increase with concentration
- Hydrolysis: slight increase with concentration
What is hydrolyzed after internalization of LDL?
Apolipoprotein B
What are the effects of increasing LDL concentration in normal cells during cholesterol synthesis, and cholesterol esterification?
- Cholesterol synthesis: decrease with concentration
- Cholesterol esterification: increase with concentration
What are the effects of increasing LDL concentration in FH cells during cholesterol synthesis, and cholesterol esterification?
- Cholesterol synthesis: no decrease with concentration
- Cholesterol esterification: no increase with concentration
What happens when you remove LDL in terms of HMG-CoA reductase activity in normal cells and FH cells?
- Normal cells: increase in HMG-CoA reductase activity
- FH cells: no response
What happens when you add LDL in terms of HMG-CoA reductase activity in normal cells and FH cells?
- Normal cells: rapid decrease in HMG-CoA reductase activity
- FH cells: no response
What is the cause of FH?
The absence of the LDL receptor
What are the four classes of LDLR gene mutations?
- Synthesis
- Transport from ER to Golgi
- Binding of LDL
- Clustering in coated pits
Which class of LDLR gene mutation can bind to LDL and be saturable as well?
Clustering in coated pits
Why are there multiple factors that can be affected by gene variations in the LDL receptor?
Because it is a multi-domain protein, so there are many things that can be affected
What apolipoprotein is the protein found in LDL? What kind of cholesterol?
- Apo B-100
- Cholesterol linoeoleate
What is the pathway of cholesterol in a hepatocyte?
- Binds to a receptor
- Internalization
- Lysosomal hydrolysis
- Release of cholesterol to the ER
- Regulatory actions
What are the regulatory actions caused by the internalization of cholesterol?
- Decrease in HMG-CoA
- Increase in ACAT for cholesterol esterification
- Decrease in LDL receptors
What form is cholesterol under following esterification?
Cholesterol oleate
Which apolipoprotein requires a APO B/E receptor in the liver?
LDL
What receptor causes familial hypercholesterolemia?
APO B/E receptor
What can cause Metabolic Syndrome?
- Genetic disorders in Apo A-II in HDL
- Genetic disorders in the CD36 receptor for fatty acids
What are the mechanisms for cellular homeostasis in cells other than hepatocytes if cholesterol concentration increases?
- ACAT converts cholesterol into CE
- Cholesterol travels to the membrane in hopes of being transferred to HDL
- Decrease in LDLR
- Decrease in HMG-CoA reductase
In which organelle is most cholesterol found in a cell?
The ER
Which transporter functions to help cells get rid of cholesterol from their membrane onto HDL?
ABCA1
What is the sterol response element?
A short and specific DNA sequence located in the promoter region of genes
What is the expression of SRE increased by? What is it decreased by?
- Increased by cholesterol depletion
- Decreased by cholesterol excess
What is the sterol response element?
Short and specific DNA sequence located in the promoter region of genes whose expression is increased by cholesterol depletion, and decreased by cholesterol excess
What is the result of adding this sequence to the promoter region of other genes? Give an example.
Confers sensitivity to cellular cholesterol status in the same way as HMGR and LDLR genes
What is SREBP?
A protein that binds specifically to the SRE sequence and stimulates transcription (transcription factor)
What is the binding of SREBP to SRE dictated by?
By the concentration of unesterified cholesterol within the cell
When are SREBPs activated?
In response to decreased cellular cholesterol concentration
Where are SREBPs located?
On the ER membrane
What are the three isoforms of SREBP?
- SREBP-1a
- SREBP-1c
- SREBP-2
Which isoforms of SREBP are encoded by the same gene?
- SREBP-1a
- SREBP-1c
What genes does SREBP-1a regulate?
Potent activator of all SREBP responsive genes
What genes does SREBP-1c regulate?
Regulates genes involved in fatty acid synthesis
How does SREBP-1c compare to SREBP-1a?
SREBP-1c is a weak activator compared to SREBP-1a
What genes do SREBP-2 regulate?
Regulates genes involved in cholesterol synthesis
What is the function of the transmembrane domain of SCAP?
Sterol-sensing transmembrane domain
What is the function of the C-terminal end of SCAP?
Interacts with SREBP
What is the function of Insig-1?
Retains the SREBP-SCAP complex in the ER when cholesterol is high
Explain what happens to SREBP when cholesterol is low.
- Change in Insig-1 conformation, allows SREBP-SCAP complex to travel to the Golgi
- Proteases on the Golgi cleave the DNA-binding domain from the complex
- DNA-binding domain travels to the nucleus and binds to SRE
The DNA-binding domain of SREBP induces the expression of what responsive genes when it binds to SRE?
- HMG-CoA reductase
- LDLR
What is the function of the S1 protease?
Cuts the luminal link of SREBP
What is the function of the S2 protease?
Cuts the linkage between the DNA-binding domain and the transmembrane domain
Which protein is an ER resident protein?
Insig
Which proteins in the SREBP molecular mechanism have cholesterol-sensing domains?
- Insig
- SCAP
What can calcium modify in terms of cholesterol overall?
- The way cholesterol can regulate the activation of SREBP
- Allows the cholesterol to move into the ER so that the cell can read the concentration of cholesterol
What characteristic allowed Brown and Goldstein to use skin fibroblasts?
The fact that cholesterol metabolism using the LDL receptor is present in all cells of the body
What is the role of cholesterol within the ER?
Plays a role in activating gene expression
The removal of cholesterol causes the expression of the ____ genes.
SRE