Lecture 5: Cholesterol Flashcards
What is cholesterol and how is it made?
Cholesterol is a type of lipid. It is an essential component of human cell membranes.
• 20-30 enzymes are required to make cholesterol.
• The first 3 are the most important.
How is cholesterol metabolism controlled on a transcriptional level?
Cholesterol metabolism is controlled through SREBP2 (sterol response element binding protein).
• If cholesterol levels are low, HMG-CoA reductase and low-density lipoprotein receptor (LDLR) are upregulated.
• SREBP2 is a 120 kDa precursor protein which is anchored to the ER. It has 2 membrane spanning helices. It has a hairpin orientation in the membrane. The N-terminal TF region and C-terminal region both face the cytoplasm.
• SCAP (SREBP2 cleavage-activating protein) has an 8 TM sterol sensing domain. Its C-terminus forms a complex with SREBP2. It can also reversibly bind to INSIG (insulin induced gene protein) which is localised to the ER.
Low cholesterol
• In a low cholesterol situation, INSIG and SCAP do not bind.
• SCAP undergoes a conformational change, exposing a MELADL sequence (it normally detect cholesterol). This signals it to be taken as part of the COPII vesicles.
• SCAP drags SREBP along with it. In the Golgi, SREBP2 is cleaved by serine 2 protease in order to release the N-terminal BHLH domain. This domain moves to the nucleus and starts transcription of sterol response element proteins.
High cholesterol
• Cholesterol binds to the SCAP on the MELADL sequence.
• SCAP and INSIG bind.
• SREBP2 and SCAP are kept in the ER.
How does the low-density lipoprotein receptor work?
LDLR binds to LDL via apoprotein B100 (apoB 100).
• LDL binds to a clathrin coated pit.
• Endocytosis then occurs.
• The LDL becomes part of the endosome.
• Proton pumps lower the pH and cause dissociation from the ligand.
• The LDLR fold back on itself. Components are recycled.
• The cholesterol moves to the ER. HMG CoA reductase is downregulated. Acetyl CoA cholesterol acyltransferase (ACAT) forms cholesterol esters from cholesterol.
• NPC2 binds cholesterol in the lysozyme and transfers it to NPC1 in the membrane, which sends it to the ER.
