Mouse models of dyslipidemia and atherosclerosis – focus on PCSK9 Flashcards
What is the exogenous pathway for lipids and lipoproteins?
Food => intestine => chylomicrons => bloodstream (free fatty acids to tissues via lipoprotein lipase) => chylomicron remnants => liver (via remnant receptors)
What is the endogenous pathway for lipids and lipoproteins?
Cholesterol synthesis => VLDL => bloodstream (free fatty acids via lipoprotein lipase) => LDL => liver or peripheral tissues (via LDL receptors)
Most of the cholesterol comes from the liver and not from food (so more of the endogenous pathway than the exogenous)
Which lipoproteins can go into arterial intima (good and bad ones)?
Bad: chylomicron remnants, VLDL and LDL
Good: HDL
(chylomicrons can’t because they are too big)
What type of lipoprotein is the primary driver of atherosclerosis?
Low-density lipoprotein (LDL)
What is PCSK9 and what does it do and what is the consequence of its action?
A protein regulating cholesterol homeostasis
Induces lysosomal degradation of LDL receptors
Leads to increases levels of cholesterol in the bloodstream
What are the 2 different types of PCSK9 mutations and what do they cause?
• Gain-of-function mutations: Cholesterol ↑
=> more and better PCSK9 => less LDLR
• Loss-of-function mutations: Cholesterol ↓
=> less PCSK9 => LDLRs are saved
What are the two types of PCSK9 inhibition?
- Monoclonal antibodies approved for use
* Anti-PCSK9 siRNA in clinical trials
How to make mice hypercholesterolemic?
Apoe -/-: high VLDL (because no remnant receptor or LDL receptor binding)
Ldlr -/-: low VLDL (because no LDL receptors)
In both cases there is no spontaneous plaque rupture
What bio-molecular technique is used to induce hypercholesterolemia mice?
Cre-LoxP technique can be utilized to develop inducible hypercholesterolemia models
Either excise the Apoe gene or excise the STOP codon of PCSK9
