Atherosclerosis, Lipoproteins And Lipid-Lowering Agents Flashcards
Define the term ‘arteriosclerosis’
Arteriosclerosis is a term used to describe thickening and loss of elasticity of the arteries => reduced lumen diameter + increased the likelihood of vessel rupture. The two types of arteriosclerosis are arteriolosclerosis and atherosclerosis.
Define the term ‘atherosclerosis’
Atherosclerosis is a progressive, inflammatory disease of large and medium sized arteries. It is characterised by focal accumulation of lipid in the vessel intima with an associated inflammatory and smooth muscle infiltrate.
List some of the non-modifiable and modifiable risk factors for atherosclerosis
N-M:
- Age
- Sex (men>women before menopause)
- Genetic predisposition based on family history
M:
- Smoking
- Hypertension
- Hyperlipidaemia (high LDL, low HDL) or dyslipidaemia (LDl/HDL imbalance irrespective of their absolute values)
- Physical inactivity
State and describe the steps involved in the development/pathogenesis of atherosclerosis
(Step 1)
- Endothelial dysfunction:
- Chronic endothelial cell injury can occur as a result of cigarette smoking and high levels of cholesterol (particularly LDL), leading to metabolic dysfunction and structural changes.
- Damage activates endothelial cells, upregulating inflammatory adhesion molecules (e.g. ICAM-1) and promoting monocyte and platelet adhesion.
- This upregulation is also caused by altered gene expression at sites where the pattern of blood flow is altered, such as bends and bifurcation in vessels.
- Injury increases permeability to lipids and LDL, allowing their accumulation in the intima.
State and describe the steps involved in the development/pathogenesis of atherosclerosis
(Step 2)
- Formation of a fatty streak:
- Monocytes adhere to the endothelium, migrate into the intima (between endothelial cells and internal elastic lamina) and differentiate into macrophages.
- Local oxidation of LDL attracts macrophages, and once in the intima, macrophages take up the oxidized LDL and become foam cells.
- Platelets adhere to activated endothelial cells or areas of denuded matrix and become activated.
- Activated platelets, activated endothelial cells and macrophages release platelet-derived growth factor (PDGF) stimulating smooth muscle cell migration from the media to the intima.
State and describe the steps involved in the development/pathogenesis of atherosclerosis
(Step 3)
- Development of lipid plaque:
- Smooth muscle proliferation and an increase in extracellular matrix occur in the intima (due to disruption of the internal elastic lamina).
- Additional cytokines and growth factors produced by activated macrophages and platelets promote additional monocyte and smooth muscle infiltration.
- Lipid may also be released from dying foam cells, contributing to extracellular free lipid pools.
State and describe the steps involved in the development/pathogenesis of atherosclerosis
(Step 4)
- Advanced plaques:
- An advanced atherosclerotic plaque consists of a lipid rich ‘core’ and a fibrous ‘cap’.
- The core of the lesion (which can become necrotic) consists of free lipid, macrophages, smooth muscle cells and cellular debris.
- The fibrous cap is composed primarily of collagen and lies over the core, beneath the endothelium.
A stable advanced atherosclerotic plaque is likely to remain asymptomatic for years. Why? When is an aneurysm created?
Initially, as the plaque expands it causes remodelling of the media allowing the vessel to increase its diameter, accommodating the plaque without compromising the vessel lumen thus allowing adequate organ perfusion.
If the enlargement is beyond proportion to the atheroma thickness, then an aneurysm is created
The atherosclerosis remains asymptomatic until what happens?
Until the atheromatous plaque ulcerates/ruptures => immediate blood clotting at the site of the ulcer; clot enlargement may partially or completely obstruct the flow of blood => tissue infarction
Summarise the exogenous lipid transport and metabolism pathway
- Dietary triglycerides are hydrolyzed to FFAs and monoacylglycerol by intestinal lipases and emulsified with bile acids, cholesterol, and fat soluble vitamins to form micelles which are transported into the enterocytes
- The absorbed fatty acids and monoacylglycerols are utilised to synthesise triglycerides; catalysed by monoacylglycerol acyltransferase (MGAT) and diacylglycerol transferase (DGAT). The absorbed cholesterol is esterified to cholesterol esters by acyl-CoA cholesterol acyl transferase (ACAT). The triglycerides and cholesterol esters are assembled with apolipoprotein B-48 into nascent chylomicrons
- Chylomicrons are secreted into the lymph (a process that depends heavily on apolipoprotein B-48) and delivered via the thoracic duct to the circulation (bypasses portal circulation)
- In the blood stream, nascent chylomicron particles interact with HDL particles resulting in HDL donation of apolipoprotein C-II and apolipoprotein E to the nascent chylomicron. The chylomicron at this stage is then considered mature.
- In muscle and adipose tissue lipoprotein lipase (LPL) is expressed at high levels; activation of LPL by Apo C-II, carried on the chylomicrons, leads to the hydrolysis of the triglycerides that are carried in the chylomicrons => formation of free fatty acids, which can be taken up by the adjacent muscle cells and adipocytes for either energy production or storage
- The hydrolyzed chylomicrons are now called chylomicron remnants (decreased in size). These chylomicron remnants are cleared from the circulation by the liver. The Apo E on the chylomicron remnants binds to the LDL receptor and other hepatic receptors to be taken up by the hepatocytes.
- In the liver they undergo lysosomal degradation, and are either used for a variety of purposes including remanufacture into new lipoproteins, production of cell membranes or excretion as bile salts
Summarise the endogenous lipid transport and metabolism pathway
While chylomicrons are responsible for transport of dietary lipids, VLDLs, intermediate-density lipoproteins, low-density lipoproteins (LDLs), and HDLs are instead involved in the metabolism of endogenously produced lipids. Triglycerides and cholesterol produced by the liver combine with phospholipids, apo B-100, and apo B-48 to form VLDLs. When secreted from the liver, VLDLs acquire the apo C and apo E from HDL. VLDL apo C-II activates lipoprotein lipase located in the capillary beds, where once again triglyceride hydrolysis takes place with the production of free fatty acids and glycerol. The VLDL molecules remaining after hydrolysis of VLDL triglycerides are either removed from the circulation by the liver or undergo further transformation by lipoprotein lipase and/or hepatic lipase to form intermediate-density lipoproteins and LDLs. LDLs, which are relatively depleted of triglyceride and enriched in cholesteryl esters and phospholipid, circulate in the blood and bind to specific LDL receptors that are widely distributed throughout tissues in order to deliver cholesterol. HDLs produced by the liver play an important role as donors and acceptors of apo C, apo E, and various lipids from other lipoproteins in the circulation.
Describe the process of reverse cholesterol transport
This process involves the mobilization of cholesterol from the plasma membranes of cells along the arterial walls and the delivery of the cholesterol to the liver in the form of cholesterol esters (CE)*, thus reducing cholesterol levels in the periphery and thereby reducing inflammation as well as atherosclerosis.
Most cells do not have a mechanism for catabolising cholesterol.
*Cholesterol is transported via HDL; HDL begins as a lipid-deficient precursor which transforms into lipid-rich lipoprotein.
State some different drug therapies that have been used to treat high cholesterol.
Bile acid sequestrants
Nicotinic acid
Fibrates
Statins
Describe the mechanism of action of statins.
They are HMG CoA reductase inhibitors.
HMG CoA reductase is the rate-limiting step in cholesterol synthesis. When inhibited, the liver compensates for the decreased cholesterol synthesis by increasing LDL receptor expression, which decreases plasma levels of LDL.
What are two important products of the cholesterol synthesispathway?
Geranyl pyrophosphate
Farnesyl pyrophosphate
They are involved in the modification and activation of proteins
