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What are the basic characteristics of cholesterol? What form is it found in?
Cholesterol: component of all cell membranes.
Required for synthesis of hormones (estrogen, progesterone, testosterone, adrenal corticosteroids).
Comes from dietary sources and liver cells.
Dietary cholesterol produces small amt of cholesterol - inhibit endogenous cholesterol synthesis - dietary saturated fat increases circulating LDL. Most dietary cholesterol is unesterified - cholesteryl esters are hydrolyzed by intestinal esterase - free cholesterol is solubilized by bile-salt micelles for adsorption.
What is the major target of drugs that lower cholesterol? What is the best time of day to administer these drugs?
Major target is HMG-CoA reductase (rate limiting in cholesterol synthesis). Nighttime cholesterols synthesis increases, drug is most effective at night.
Describe the structural features of lipoproteins.
Lipoproteins are assembled TGs, cholesterol, and cholesterol esters that are usually insoluble that assemble with phospholipids and apoproteins to form lipoproteins.
Hydrophobic cores: TGs and cholesteryl esters.
Hydrophilic surfaces: cholesterol, phospholipids, and apolipoproteins (recognition sites).
What are the five common lipoproteins found in the human plasma? What are their common characteristics?
Chylomicrons have the highest molecular weight, least density, and are high in TAGs. VLDLs are of medium weight 10-80; slightly higher density than chylomicrons and consist highly of TAGs. IDLs have MW of 5-10, higher density, and highly consist of TAGs and cholesterol. LDLs have a MW of 2.3, higher density and consist of protein and cholesterol. HDLs MW is 0.18-0.36 and have a high density; they consist of protein, cholesterol, and phospholipids.
What are some of the defining characteristics of HDL?
Major apoprotein ApoA-1 (from liver/intestine; functions to activate LCAT, cholesterol efflux via ABCA1) and ApoA-2. Protects against CAD. Increased by exercise and moderate alcohol intake.
How do women maintain high HDL levels compared to men?
Women have higher HDL because it is partially managed by estrogen before menopause.
What are some of the defining characteristics of LDL? How is it calculated?
Major apoprotein is ApoB-100 (from liver; functions as ligand LDL receptor and TG transport from cells). Greatest contributor to CAD; role to dliver cholesterol to non-hepatic tissue.
What is the process by which LDL cholesterol fuels development of atherosclerosis?
Cholesterol moves from arteriole lumen into space that underlies arterial epithelium. The oxidized LDLs cause attraction of monocytes from circulation which undergo conversion to macrophages. Macrophage motility is inhibited and they are kept at atherogenesis sites. They take up cholesterol that hasn't been oxidized and become cytotoxic and damage endothelium (become large, vaculated as foam cells), producing a fatty streak under the epithelium, creating a lumpy arterial wall. Continuous accumulation of foam cells cause rupture, having blood platelets adhere and forming microthrombi. The end results in mature atherosclerotic lesion characterized by large lipid core and tough fibrous cap.
What are some of the defining characteristics of IDL?
Has an apoprotein of ApoE (from liver/intestine; its a ligand, LDL receptor, and LRP receptor. It consists of 50% received endogenous material from the liver and 50% LDL.
What are some of the defining characteristics of VLDL?
The major apoproteins are ApoB-100, ApoC, and ApoE (all from liver; B-100 LDL receptor, C activates LPL, E is ligand/receptor). It mainly consists of triglycerides that are digested by LPL.
What are some of the defining characteristics of chylomicrons?
Apoproteins are A1, A2, A4, and B48. These deliver lipids by hydrolysis by LPL.
What are some of the defining characteristics of chylomicron remnants?
Apoproteins are B48 and E. This delivers lipid by receptor endocytosis.
What is the role of lipoprotein lipase?
Found in endothelial cells. Hydrolyzes TAGs to FFAs and glycerol
What is the role of hepatic lipase?
synthesized and secreted by liver and binds to cell surface of hepatocytes and endothelial cells. Hydrolyzes TAGs and phospholipids
What is the role of LCAT?
Lecithin-cholesterol acyltransferase synthesized by liver and secreted into circulation. Esterifies cholesterol in plasma and promotes the formation of HDL.
Describe the exogenous pathway of lipoprotein metabolism.
The exogenous pathway for lipoprotein metabolism refers to what is coming into the body from external sources. This includes dietary fat, which is absorbed by the intestines and formed into chylomicrons, in which triglycerides are higher than cholesterol esters. These contain E, C, and B-48 receptors. These chylomicrons are digested by lipoprotein lipase (yielding Free Fatty Acids for adipose tissue), and the remnants of this contain higher cholesterol esters than triglycerides (which were just broken down). This contains receptors E and B-48, which is recognized by the liver. The liver in the exogenous pathway secretes bile acids and cholesterol for assistance in the digestion of dietary fat.
Describe the endogenous pathway of lipoprotein metabolism.
The endogenous pathway is involved in internally excreted compound, particularly from the liver. Very-low density lipoprotein is secreted from the liver, in which triglycerides levels are higher than cholesterol esters. Receptors, E, C, and B-100 are present. These are digested by lipoprotein lipase, yielding FFA for adipose tissue, yielding IDL (intermediary), in which cholesteryl esters are higher than triglycerides (and receptors E and B-100 are present). These are then converted into LDL, which only contains B-100 receptors, which are absorbed by the liver, or carried into extrahepatic tissues. Eventually, these extrahepatic tissues die and release HDL cholesterol (containing A1 and A2 receptors). Plasma LCAT (lecithin: cholesterol acyltransferase) converts it back into IDL, which continues the pathway to the liver in which LDL is disposed of by HDL.
Describe the reverse cholesterol transport pathway.
Reverse cholesterol transport: process by which excess cholesterol in peripheral cells (foam cells esp), is returned to the liver for degradation and excretion
Involves apoA-1, ABCA1, LCAT, and receptors on the liver for uptake of excess cholesterol. SR-A1 reconizes modified/oxified LDL and internalizes it. Accumulation of modded LDL in cells leads to accumulation of lipid droplets in macrophages and formation of foam cells.
What are some risk factors for development of CHD?
LDL/HDL ratio above 3.0, Total C/HDL above 4, TG/HDL above 2
What are some positive risk factors for atherosclerosis?
Males over 45 and females over 55. Family history of early CHD, Elevated LDL (over 130), elevated triglyceride (over 150), diabetes mellitus, hypertension, obesity, smoking, and CHD.
What are some negative risk factors for atherosclerosis?
High HDL, low LDL, good genes, female gender, and exercise
What is the role of Lp(a) in atherogenesis?
Lp(a) is an independent risk factor and is highly heritable
A lipoprotein particle that consists of an apo(a) molecule covalently linked by disulfide bond to apoB-100 (component of LDL-like molecule)
Certain SNPs of LPA gene associated with higher population CV risks levels
What are screening criteria for classification by total plasma cholesterol?
Serum total C should be measured once every 5 years, screening made in nonfasting state, and may prompt either periodic re-screening or initiation of dietary modification program
What are some risk factors that constitute metabolic syndrome?
Abdominal obesity, TG levels above 150, low HDL, elevated blood pressure over 130/85, fasting blood sugar over 100
What is the role of the ABCA1 transporter?
This is a large plasma membrane ATP dependent protein. Needed to move excess cholesterol and phospholipid to plasma membrane. Acts as flipase, flipping cholesterol and phospholipid from inner to outer leaflet. needed to remove excess cholesterol from foam cells and prevents early steps of atherosclerosis. ApoA-1 is required for capturing the cholesterol released from foam cell.
What are hyperlipoproteinemias?
Hyperlipoproteinemas are conditions in which the concentration of cholesterol carrying lipoproteins in plasma exceed ARBITRARY NORMAL LIMIT (95% of population)
Accelerated concentration of lipoproteins accelerate development of atherosclerosis
How is Alzheimer's linked with lipoproteins?
