Block 2 - Dyslipidemia Physiology Flashcards
What is the leading cause of stroke and death?
High blood cholesterol raises the risk for heart disease
What are the types of inherited HLD?
What are symptoms of HLD?
None
What are the signs of HDL?
None or eruptive xanthomas
What is cholesterol?
Important constituent of cell membrane with rigid ring system and a short branched HC tail
Hydrophobic
OH making it amphipathic
How much of cholesterol is synthesized by the liver?
80%
How is cholesterol synthesized?
the liver from acetyl-coA which is inhibited by hepatic LDL uptake
Where is dietary cholesterol found?
Animal fat and enterohepatic circulation
What are the functions of cholesterol?
- Serves as a component of cellular membranes
- Precursor to steroid hormones and bile acids
- Storage and transport → cholesterol esters
How is cholesterol absorbed from the GI?
Intestinal cholesterol transporter
Describe the biosynthesis of cholesterol?
LDL receptor pathway: Reduction of HMG-CoA by HMG-CoA reductase → mevalonate
Rate limiting step and site of drug action
What are the classes of lipoproteins?
- Chylomicrons
- Very low density lipoproteins (VLDL)
- Intermediate density lipoproteins (IDL)
- Low density lipoproteins (LDL)
- High density lipoproteins (HDL)
What are lipoproteins?
Particles found in plasma that transport lipids and cholesterol serving as a transporter between tissues
What are the components of lipoproteins?
- Triglycerides (TG)
- Esterfied cholesterol (CE)
- Monolayer of phospholipids and apolipoproteins
What are the large apolipoproteins?
apoB (B-48 and 100) = atherogenic
What are the small apolipoproteins?
apoA-I, apoC-II, apoE
LP for A-1?
HDL
LP for B-48?
chylomicrons
LP for B-100?
LDL
LP for C-2?
Chylomicorns, VLDL, HDL
LP for E?
Chylomicrons, VLDL, IDL HDL
What are lipoproteins metabolic functions?
- Exogenous (chylomicron) pathway
- Endogenous pathway
- HDL metabolism & reverse cholesterol transport (Apolipoprotein transfer and cholesteryl ester transfer)
What is the difference between exogenous and endogenous pathways?
Ex: Dietary fat
Endo: Lipids are synthesized and processed by the liver
What 2 problems must be overcome to digest lipid? What is the solution?
- Lipids are not soluble in aqueous solutions
- Lipid hydrolysis products aggregate and form large complexes that make poor contact with the cell surfaces
Overcome by the formation of chlomicrons
What is the the average adult intake of fat?
60–160 g of fat per day
Describe the steps of the exogenous pathway?
Describe the process of chylomicron metabolism?
- Long-chain FA are re-esterified → TAGs in gut → transferred to chylomicron contains apoB48
- Chylomicrons are synthesized in the intestines and secreted into the blood via the lymphatic circulation
- apoA’s, apoC’s, apoE and cholesteryl esters are acquired from HDL in the circulation
- In the circulation, apoC-II activates lipoprotein lipase found on the capillary walls of the endothelium
- Lipoprotein lipase catalyses the hydrolysis of triacylglycerol into free fatty acids that are taken up and utilized by various tissues
- Apolipoproteins are transferred back to HDL
- The chylomicron remnant is taken up by the apoE / Remnant Receptor in the liver
How are are VLDL synthesized?
Triglycerides (TG) and cholesterol synthesized in the liver are transferred to VLDL which contain** apoB-100**
How is VLDL metabolized?
- apoC’s, apoE and cholesterol esters are acquired from **HDL **in the circulation leading to formation of the mature VLDL in plasma
- ApoC-II on VLDL activates lipoprotein lipase which catalyses the hydrolysis of triglycerides to free fatty acids which are taken up by muscle, adipose and hepatic tissues
- **VLDL ** has released its cargo, apolipoproteins are transferred back to HDL
- The end product is an apoE containing VLDL remnant (or IDL)
What are the outcomes of VLDL?
- Remnant uptake
- Conversion to LDL
How does VLDL remnat uptaked?
The remnant particles (or IDLs) containing apoE, are taken up by the apoE / remnant receptor in liver and removed from circulation
How id VLDL converted to LDL
Further action on IDL by hepatic triglyceride lipase causes loss of apoE’s and the particle is converted to LDL containing apoB-100
How much of IDLs are converted to LDLs? How much of LDL are recycled by the liver?
40%, 60%
What are the componets of LDL?
- Surface Monolayer
Made of phospholipids, Cholesterol and Protein (apoB-100) - Hydrophobic Core: Triglyceride (5%) Cholesteryl Esters (35%)
How much of cholesterol is carried by LDL in the blood?
70%
How is LDL metabolized?
- LDL is removed from the plasma by the apoB-100 / LDL receptors, which are mainly expressed in liver
- LDL with Apo B-100 are taken up by the LDL Receptor into clathrin-coated pits
- LDL dissociates from the receptor and the receptor may recycle to the membrane
- In the lysosome, lipids are de-esterified and released as free cholesterol into the cytosol; lipoproteins are hydrolyzed and amino acids are recycled
What are the outcomes of LDL being metabolized?
- Increase in free cholesterol -> decreased LDL recepotr synthesis
- Increased cholesterol esterfication for VLDL or excretion in bile
Wht can LDL receptors defect lead to?
Familial hypercholesterolemia
What do non-recpetor mediated uptake lead to?
Risk for arthrosclerosis
How does LDL receptor acitvity control cholesterol hoemostasis?
- High cholesterol leads to repression of IDL and LDL receptor synthesis and maintenance of elevated plasma LDL levels
- Liver removes IDL and LDL from serum, therefore the number of IDL and LDL receptors on liver plays a direct role in cholesterol hemostasis
How is HDL metabolized?
- HDL originates from lipid poor ApoA1 containing particles secreted from the liver and gut.
- Free cholesterol is acquired from peripheral tissues via ATP-binding cassette protein A1 and G1 (ABCA1 and ABCG1) mediated efflux forming Nascent HDL
- Through the actions of Lecithin-cholesterol acyl transferase (LCAT), cholesterol esters are incorporated into HDL which matures into a spherical form, HDL-3 .
- More cholesterol is acquired from peripheral tissues via SR-B1 and ATP-binding cassette protein A1 and G1 (ABCA1 and ABCG1) mediated efflux, forming the mature HDL-2
What are the 2 fates of HDL particles?
- Cholesteryl ester transfer protein (CETP) – mediates export of cholesteryl esters from HDL into apo B-containing lipoproteins (LDL, VLDL) in exchange for triglycerides, which can then be taken up by the LDL receptor in lever and excreted in bile.
- HDL particles at the liver release cholesterol to hepatocytes via scavenger receptor class-B, type I (SR-BI) for recycling or excretion in the bile
What is reverse cholersterol transport?
free cholesterol (FC) is removed from cells, such as macrophages in arterial walls, and returned to the liver for excretion to protect the body from atherosclerosis
What is found on a HLD lipid panel?
How do calculate total cholesterol?
(TC) = LDL + HDL + (Triglys/5)
How do you solve for LDL? Why is this not used?
[LDL]CALC = TC – (HDL + (Trigly/5))
- Inaccurate at high triglyceride and total cholesterol levels
- Non-HDL and Lp(a) are now newer targets of the ACC/AHA Guidelines
What are the benefits of lowering cholesterol?
improves cardiovascular outcomes
How does atherosclerosis develop?
- LDL Oxidation and modification
- Stimulation of monocytes
- Monocytes form Macrophages
- Macrophages ingest the modified LDL and become Foam Cells
- Foam cells attract T-Lymphocytes that create a chronic inflammatory reaction
Describe role of LDL in atherosclerosis? SLIDES 67-72
What cholesterol type is associated by coronary heart disease and DM?
Small dense LDL
Why are antioxidants beneficial against LDL?
Reduces the oxidative process of LDL due to its susceptiblity to oxidation
How does large buoyatn LDL differ from small dense?
Less atherogenic
What converts small LDL to large?
Niacin
What happens at the begining of endothelial dysfunction?
- Increased endothelial permeability to lipoproteins and plasma constituents.
- Up-regulation of leukocyte and endothelial adhesion molecules allowing infiltration of monocytes.
Wht are the labs associated with atherogenic dyslipidemia?
- ELevated TG
- Reduced HDL
- Elevated LDL
- Increased oxidation of LDL
What occurs at the beginning of Endothelial Dysfunction?
- Increased endothelial permeability to lipoproteins and plasma constituents.
- Up-regulation of leukocyte and endothelial adhesion molecules allowing infiltration of monocytes.
What forms a fatty streak?
- Smooth muscle cell migration
- Macrophage foam-cell formation.
Describe the formation of a fibrous cap?
- Fibrous cap forms in response to injury.
- Fibrous cap covers a mixture of leukocytes, lipid and debris which form a necrotic core.
- Necrotic core results from foam cell accumulation, apoptosis and necrosis, increased proteolytic activity and lipid accumulation.
What is thrombosis?
Rupture or ulceration of fibrous cap rapidly
Where does thrombosis occur?
- sites of thinning of the fibrous cap
- continuing influx and activation of macrophages which release proteolytic enzymes
- enzymes degrade the matrix which can lead to further hemorrhage and thrombus formation
What is coronary artert thrombosis?
final pathogenic mechanism of acute ischemic events, including myocardial infarction and sudden cardiac arrest
What occurs during coronary artery thrombosis?
Plaque rupture exposes thrombogenic subendothelial components, leading to platelet deposition and activation
What lipoprotein is know to be cardioprotective?
High levels of HDL
Describe the role of HDL? SLides 84-86
What is lipid lowering not the only solution for treating atherosclerosis?
- Inflammatory disease
- 35% of patients with cardiovascular disease do not have hypercholesterolemia
- Lipid accumulation is NOT the ONLY cause of atherosclerosis
What is CRP?
Major component of the acute phase inflammatory response and marker of bacterial infection.
How is CRP expressed?
mainly by liver hepatocytes and induced by IL-1β and IL-6
What are thromogenic risk factors?
- Increased fibrinogen
- Increased Factor VII
