CVD: Exploring the roles of lipoproteins HDL and LDL Flashcards
What are the distinct lipoprotein populations?
- Chylomicrons
- VLDL (very low density lipoproteins)
- IDL (intermediate density lipoproteins)
- LDL (low density lipoproteins)
- HDL (high density lipoproteins)
What are lipoproteins comprised of?
- A core of TG, cholesterol esters, and fat-soluble vitamins.
- A monolayer membrane of phospholipids and small amounts of free cholesterol.
- Proteins called “apoprotein”
What are the different apoproteins?
- “integral” apoproteins, such apoA or apoB, penetrating as a transmembrane protein through the monolayer membrane (at the core and are structural)
- “peripheral” apoproteins, such as apoC or apoE, remaining at the surface of the phospholipid membrane (superficial and bring the proper transporters)
Lipoprotein composition and characteristics
What are the pathways of lipoprotein and lipid transport?
- Chylomicrons → exogenous pathways
- LDL → endogenous pathway
- HDL → reverse transport pathway
exogenous pathway of chylomicrons
- CMs transport dietary fat to adipose tissue and liver. Our intestines package cholesterol, fats, and fat-soluble nutrients and vitamins into CMs in the enterocyte cell lining the small intestine.
- CMs comprise the integral apoB-48 (a shortened form of apoB-100, being approximately 48 percent as long).
- Chylomicrons enter the lymphatic circulation and make their way via the thoracic lymph duct to the circulation where the duct empties into the subclavian vein in the neck.
- In the blood stream CMs acquire two peripheral apoproteins: apoC and apoE. They travel either to the liver or adipose tissue
- CM remnants are cleared from the circulation by the liver cell (hepatocytes) via the chylomicron remnant receptor on the hepatocytes, binding to the apoE on the remnant particle. The liver then makes use of the remaining triglycerides.
apoC vs. apo E
- In the liver the hepatocytes binds the apoE via the LDL receptor (LDL-R) on the surface of the hepatocytes and CMs are taken into the liver cell where the triglycerides will be used in metabolism.
- Adipocytes bind the apoC via lipoprotein lipase (LPL), thus depleting the chylomicron of triglyceride content and filling the fat cell with fatty acids. When triglyceride is reduced to ~ 20% in the chylomicron the apoC dissociates from the chylomicron and this reduced triglyceride lipoprotein with only apoB48 and apoE is now called a “chylomicron remnant”.
Endogenous pathway of LDL
- VLDL lipoproteins are made by the liver for the purpose of transporting fat from the liver to other tissues. They carry TGs, cholesterol esters and one apoB100 apoprotein.
- Like CMs, VLDL acquire two further apoC and apoE surface apoproteins, and bind adipocytes via the apoC.
- As the triglyceride levels in the VLDL drop to 50%, the VLDL dissociates from the LPL and returns to the liver.
- If the VLDL stays attached longer to adipocytes and its TG stores deplete to 30%, the lipoprotein becomes an IDL molecule
- If the IDL molecule depletes its TGs to 10% and loses the apoE and apoC peripheral apoproteins, it becomes a cholesterol ester rich LDL molecule.
- Importantly the LDL molecule does not have apoE or apoC and its apoB100 has a much lower affinity for the LDL-R on the hepatocytes. As a result the half-life of LDL in the blood is much longer than all the other lipoproteins and LDL is susceptible to oxidative modifications.
Reverse transport pathway of HDL
- HDLs are synthesized in the liver. They transport cholesterol from the tissues back to the liver for excretion into the bile.
- It is estimated that 70% of excreted cholesterol will be reincorporated with dietary fat into CMs in the small bowel.
- When synthesized, HDLs have very little TG or free cholesterol (they are essentially “empty”).
- In the circulation, empty HDLs acquire a membrane-bound enzyme called LCAT (lecithin-cholesterol-acyltransferase). LCAT attaches and extracts cholesterol esters. Loaded HDLs transport this back to the liver attaching to the apoA-receptor.
- Thus, in deficient HDL (low HDL) states there is less of these carrier molecules to unload the cells and arterial walls of cholesterol content ➔ hence an independent risk for vascular disease.
Medications
- statins
- Ezetimibe
- PCSK9
- Niacin (vitamin b3)
- Fibrates (such as clofribrate)
- Gemfibrozil
- Bile acid sequestrants (cholestyramine and colestipol)
Statins mode of action
Statins (such as Lovastatin and Mevastatin) act by competitively inhibiting HMG-CoA reductase, the first and key rate-limiting enzyme of the cholesterol biosynthesis pathway
* Statins mimic the natural substrate, HMG-CoA, and thus compete for binding to the HMGCR enzyme but cannot be processed so inhibits de nova synthesis of cholesterol.
What is significant about statins?
Inhibition of HGMCR is significant because most circulating cholesterol comes from internal manufacture rather than the diet. In addition, hepatocytes sense the reduction in liver cholesterol with statin use and compensate by synthesizing more LDL receptors on the cell surface, resulting in increased cholesterol uptake.
* Effective and recommended as first line therapy.
* Well tolerated (liver toxicity).
Mode of action for Ezetimibe
Ezetimibe works by blocking the absorption of cholesterol uptake at the brush border of the enterocytes, and thus reduces the amount of cholesterol/cholesterol ester to be incorporated into chylomicrons.
* Effectiveness is inconsistent.
* Adverse effects include steatorrhea.
* predicted to have minor effects since most cholesterol is endogenously produced
Mode of action for Pcsk9
PCSK9 inhibitors are a newer class of drugs that have been shown to dramatically lower LDL cholesterol levels.
* They aim at inhibiting a protein called Proprotein convertase subtilisin kexin 9 (PCSK9).
* Since PCSK9 targets LDL-R for degradation, the net result is an increase in the amount of LDL-R at the cell surface
* PCSK9 inhibitors may also induce the expression of LDL-R.
* PCSK9 inhibitors allow increased plasma clearance of LDL accounting for lower plasma LDL and thus less cardiac risk.
How do statins and Pcsk9 compare?
