Cholesterol Metabolism Flashcards
What are some the functions of cholesterol?
- Essential components of cell membranes
- Precursor for bile salts
- Precursor for steroid hormones
- Regulates the activity of proteins
What part of cholesterol gives it its amphipathic qualities?
The hydroxyl (OH) group
What are the different sources of cholesterol?
- Endogenous sources (major source)
- Dietary sources
What are some examples of endogenous sources of cholesterol?
The liver synthesizes 1 gram of cholesterol daily
What are some examples of dietary sources of cholesterol?
- Egg
- Cheeseburger
- etc…
How do clinical drugs reduce cholesterol levels?
They target both endogenous and dietary sources of cholesterol
Giver a BRIEF overview of cholesterol biosynthesis
- Occurs predominantly in the liver
- Increased by insulin and reduced by glucagon
- Biosynthetic enzymes = in the cytosol
Why are cholesterol biosynthetic enzymes found in the cytosol?
Allows you to segregate biosynthetic products (which require energy) from energy producing products
What is the first stage in cholesterol biosynthesis?
Acetyl-CoA —> HMG-CoA —> Mevalonate
- Acetyl-CoA must make its way from the matrix to the cytoplasm (how does it do this?)
- In the cytoplasm acetyl-CoA is converted to isoprene units
- HMG-CoA is made from 3 molecules of acetyl-CoA by HMG-CoA synthase
- HMG-CoA reductase takes HMG-CoA and turns it into mevalonate
What is the second stage in cholesterol biosynthesis?
Mevalonate —> Two activated isoprene units
- 4 step reaction
Describe the 4 step reaction that turns mevalonate into two isoprene units
- Mevalonate phosphotransferase adds the first phosphate (result: phosphomevalonate)
- Phosphomevalonate kinase adds the second phosphate (result: 5-pyrophosphomevalonate)
- Pyrophosphomevalonate decarboxylase decarboxylates and dehydrates to produce the isoprene unit (result: isopentenyl pyrophosphate)
ATP = cofactor
What is the third stage in cholesterol biosynthesis?
Condensation of 6 activated isoprenes make squalene (30C)
What is the fourth stage in cholesterol biosynthesis?
Cyclization of squalene to make lanosterol and conversion of lanosterol into cholesterol
How is cholesterol biosynthesis regulated?
- Rapid regulation
- Long-term regulation
Describe rapid regulation of cholesterol biosynthesis
Phosphorylation by AMP activated protein kinase (AMPK) inactivates HMG-CoA reductase
HMG-CoA reductase turns HMG-CoA into mevalonate
Describe long-term regulation of cholesterol biosynthesis
Regulation of HG-CoA reductase transcription
Describe the regulation of HMG-CoA reductase transcription
How is cholesterol transported to target tissues
- Dietary cholesterol is packaged into chylomicrons
- Lipoprotein lipase cleaves triglycerides in chylomicrons
- Cholesterol-rich chylomicron remnants are taken up by the liver
- In the liver cholesterol and cholesterol esters are incorporated into VLDL that are released into the bloodstream
- In the bloodstream lipoprotein lipase cleaves triglycerides in VLDL to generate LDL
- LDL is taken up by peripheral tissues by endocytosis
How is LDL recognized and taken up by peripheral tissues
- LDL receptors on tissue recognize and bind apolipoprotien B100 on LDL
Describe the structure of a VLDL
- Cholesterol = confined to the phospholipid monolayer
- Cholesterol esters = packed into the hydrophobic lipoprotein interior
What is the difference between good cholesterol and bad cholesterol?
- Bad cholesterol = LDL
- Good cholesterol = HDL
You want high levels of HDL and low levels of LDL
Why is LDL bad?
High levels of LDL circulating in the blood stream leads to atherosclerosis and coronary heart disease
What is atherosclerosis?
The hardening and thickening of arteries and restricted blood flow caused by deposition of lipids (cholesterol) within arteries
How can you reduce blood cholesterol levels?
- Diet
- Drugs
What are statins?
HMG-CoA reductase inhibitors
What does HMG-CoA reductase do?
What is another inhibitor that can Lower LDL levels?
- PCSK9 inhibitors
- PCSK9 is secreted by the liver and binds to LDL receptor and enhances its degradation by lysosomes within cells
- PCSK9 inhibitors block this function and reduce LDL receptor degradation allowing it to be recycled to the plasma membrane to take up additional LDL
