Hyperlipidemia Flashcards
What is the function of LDL?
Carries cholesterol from liver to peripheral tissues (breakdown produce of VLDL, very low TG content and high cholesterol content).
Leftover LDL is uptaken by liver LDL-R.
What is the major apoprotein expressed on LDL, and what is its function?
Apo B-100, organizes the particle and acts as the ligand for LDL removal by binding LDL-R in liver
What does HDL do?
Mediates reverse cholesterol transport by uptaking excess cholesterol from the periphery, including macrophages / foam cells, transfers it to VLDL or back to liver (B1 scavenger receptor)
What is the primary mechanism by which LDL induces thrombo-embolism?
Oxidized-LDL accumlates in arterial wall, monocytes are recruited and become macrophages -> foam cells. Foam cells are lodged in arterial wall and cause stenosis, may burst and recruit more macrophages for oxidized-LDL uptake.
If the plaque ruptures, a clot may be formed on it, which can lodge in a coronary artery (MI) or brain (stroke)
What drug inhibits the dietary intake of cholesterol and how does it do this? Is it used alone?
Ezetimibe - inhibits intestinal cholesterol transporter (NPC1L1) - typically used in combination with statins (monotherapy shows minimal cholesterol reduction)
What other pathways will be affected via statin use?
- Protein lipidation
- Coenzyme-Q formation -> underlies myopathy of statins
- Steroid hormones, vitamin D, bile acids
How does LDL-R endocytosis work and when is it upregulated?
Clathrin-mediated endocytosis once the ligand binds
Low cholesterol levels in the liver needed for bile acid synthesis and membrane maintenance signals upregulation of LDL-R and a further reduction in circulating LDL (key mechanism of cholesterol meds).
What are the two most common forms of familial hypercholesterolemia?
- Mutated LDL-R (endocytosis does not work properly)
- Mutated and upregulated PCSK9 - protease which binds LDL-R and induces its endocytosis and lysosomal degradation independent of LDL binding. -> lack of LDL-R will increase LDL and heart attack risk
What are the two PCSK9 inhibitors and who uses them? How do they work?
- Alirocumab
- Evolucumab
Used as a second line to statins when LDL remains high or statin side effects are high, but very expensive.
Increases the expression of LDL-R on liver by monoclonally binding PCSK9
How do statins work? Where do they act?
Competitive inhibition of HMG-CoA reductase, which converts HMG-CoA into mevalonate.
Act primarily in the liver, which is the major site of cholesterol storage and synthesis
What is the primary way in which statins reduce LDL-C? What does this have to do with effectiveness in familial hypercholesterolemia?
Lowered intracellular cholesterol levels lead to upregulation of LDL-R transcription, increasing LDL endocytosis
-> familial hypercholesterolemia -> LDL-R gene is mutated so there is only a minor LDL-reduction
Which two statins have the longest half-life?
Atorvastatin and rosuvastatin -> 20 hours, only need to be taking once daily. (Lipitor and crestor)
What effect do statins have on triglycerides and why?
Large reduction, often 30-50%, due to decreased VLDL production from lack of cholesterol, and scavenging of VLDL from LDL-receptor (since it also expresses Apo-B100)
What is the most common statin side effect and sub-side effect?
Myopathy - potentially due to inhibition of Co-Q10 synthesis.
Rhabdomyolysis may occur - fatal statin toxicity leading to induced muscle breakdown (Autoimmune) -> may lead to kidney failure
What metabolic syndrome do statins put you at risk for?
Type 2 diabetes, although CV risk reduction outweighs this
