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Lipoproteins are composed of
A neutral lipid core, surrounded by a shell of amphipathic apolipoproteins, phospholipids, and nonesterfied cholesterol.
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What makes the lipoproteins water soluble
The amphiphatic compounds are oriented with their polar portions exposed on the surface.
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What are the lipoproteins largest in size, lowest in density, contain the highest percent of lipid, and lowest amount of protein
Chylomicrons
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What is the order of the lipoproteins from most dense to least dense
- HDL
- LDL
- IDL
- VLDL
- Chylomicrons
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Apolipoproteins function
Provide recognition sites for cell surface receptors, act as coenzymes and activators for enzymes in lipoprotein metabolism
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Where are chylomicrons assembled
Intestinal mucosal cells
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What do chylomicrons carry
Dietary triacylglycerol (TAG's), cholesterol, fat soluble vitamins, and cholesteryl esters to peripheral tissues
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What accounts for close to 90% of the chylomicrons
Triacylglycerol (TAG's)
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What apolipoprotein is unique to only chylomicrons
Apolipoprotein B-48
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Apolipoprotein B-48 begins synthesis where
In the rough ER, and is then moved through the RER and the golgi where it is glycosylated
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Apo B-100 is made where and found on what lipoproteins
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Where are the enzymes located that synthesize tiacylglycerol, cholesterol, and phospholipids
In the ER
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What is required to assemble apo's and lipids into chylomicrons
Microsomal triacylglycerol transfer protein, which loads Apo B-48 with lipid
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What is a nascent chylomicron
A functionally incomplete protein, these are released by the intestinal mucosal cells
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What is apo C-II necessary for
They activation of lipoprotein lipase, the enzyme that degrades the triacylglycerol in chylomicrons
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What is the source for Apo C-II
Circulating HDL
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Lipoprotein lipase
Extracellular enzyme that degrades TAG's, it is anchored by heparan sulfate to the capillary walls of most tissues
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What tissues is lipoprotein lipase predominantly anchored to
- Adipose, cardiac, and skeletal
- The adult liver doesn't have it
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What happens to the free fatty acids and glycerol after being broken down by lipoprotein lipase
- Free fatty acids go to the tissues
- Glycerol goes to the liver
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When activated by apo C-II, what does lipoprotein lipase do
Hydrolyzes the triacylglycerol contained on chylomicrons, LDL, VLDL, and HDL to yield fatty acids and glycerol
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Where are the fatty acids stored
In the adipose tissues and used by muscles for energy
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What happens to fatty acids if they are not directly taken up by the cell
They are transported by serum albumin until they are taken up
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What does the liver use glycerol for
- Lipid synthesis
- Glycolysis
- Gluconeogenesis
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What happens in patients that lack lipoprotein lipase or apo C-II
They show an accumulation of chylomicrons in their plasma (hypertriacylglycerolemia)
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How is the activity of lipoprotein lipase regulated
Its synthesis and transfer to the luminal surface of the capillaries is stimulated by insulin
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Where is the highest concentration of lipoprotein lipase
In the cardiac muscle (has a small Km for it as well)
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How does the liver recognize remnants of chylomicrons to degrade them
By the apo-E on its surface
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What happens in the liver to the chylomicron remnants
The endocytosed vesicle fuses with lysosomes where the apo's and cholesteryl esters are degraded releasing amino acids, free cholesterol, and fatty acids.
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What are the events that lead to the metabolism of chylomicrons (CM)
- Intestinal mucosal cells secrete nascent CM with Apo-48 on their surface
- Apo C-II + apo-E are transferred from HDL to CM
- CM enters the capillaries
- Lipoprotein lipase degrades TAG in CM
- Apo C-II is returned to HDL (Keeps Apo E)
- CM is degraded by the liver
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VLDL's are produced where
Liver
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What is the function of VLDL's
To carry TAG's from the liver to the peripheral tissues
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What molecular activity causes fatty liver (hepatic steatosis)
Inbalance between hepatic TAG's synthesis and secretion of VLDL's
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What are some causes of fatty liver (hepatic steatosis)
- Diabetes
- Obesity
- Chronic ethanol ingestion
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VLDL's covered in apo B-100 are secreted by liver and then do what
They must obtain C-II and apo-E from circulating HDL
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After VLDL is degraded by LPL, what happens to the C and E apo's
They are returned to the HDL, but they retain B-100
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What causes the transfer of cholesteryl esters from HDL to VLDL so it can be disposed
Cholesteryl ester transfer protein (CETP)
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What are the events that lead to the metabolism of VLDL and LDL
- Liver secretes nascent TAG rich VLDL (apo B-100 on its surface)
- VLDL acquires C-II + apo E form HDL
- VLDL enters the capillaries
- TAG in VLDL is degraded by LP lipase
- Apo C-II and apo E are returned to HDL
- The liver takes up the LDL
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LDL has a lower amount of TAG's then VLDL but a higher amount of
Cholesterol and cholesteryl esters
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What is the primary function of LDL
To provide cholesterol to the peripheral tissues, or return it to the liver
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LDL surface receptors recognize
apo B-100 and apo E, but not apo B-48
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How do LDL deliver cholesteryl esters
- They bind to a plasma membrane via a clathrin coated pit
- It is internalized by endocytosis
- Clathrin coat degrades and the vesicle fuses with others making an endosome
- High pH causes LDL to separate from its receptor
- The cholesteryl esters are released as free cholesterol, fatty acids, amino acids, and phospholipids
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HMG CoA reductase does what, and is inhibited by
Sythesizes cholesterol in the cell when it doesn't have enough, it is inhibited by high cholesterol, triggered by insulin
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Synthesis of LDL receptors is inhibited by
High cholesterol
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What is the role of Acyl CoA: cholesterol acyltransferase (ACAT)
When cholesterol isn't needed for immediate structural or a synthetic purpose, it stores it in cells
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What lipoproteins are most likely to cause a Hypertriglyceridemic response
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What lipoprotein brings the dietary fats (exogenous) into the body
Chylomicrons
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What is the carrier for endogenous lipids
VLDL
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What is good about a high HDL3
It will lower the risk of heart disease
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What is apo A-I associated with
Chylomicrons and HDL, it activates LCAT (HDL esterfier)
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Apo A-II is associated with what lipoproteins
Chylomicrons and HDL, it enhances hepatic lipase activity
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LDL contains only what apo
Apo B-100
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Apo B-100 is found on what lipoproteins
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Apo C-I and C-II and C-III are found on what lipoproteins
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What is the important role of C-II
It activates lipoprotein lipase
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Apo C-III is associated with what lipoproteins and has what function
- Chylomicrons
- VLDL
- IDL
- HDL
- Inhibits lipoprotein lipase
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Apo D is found on what lipoprotein and performs what function
HDL, it is closely associated with LCAT (Esterfies cholesterol in HDL)
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Cholesterol ester transfer protein (CETP) is exclusively associated with and does what
HDL, and transfers cholesterol esters from HDL particle into VLDL and IDL that can be taken up by the liver and disposed
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Apo E associates with
- Chylomicron remnants
- VLDL
- IDL
- HDL
- Binds B/E receptors on hepatocytes and associated with Alzheimers (E4)
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Apo H is found on
Chylomicrons, for TAG metabolism
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What is the significance of Apo A-1
- It helps HDL dock on cells without a receptor
- Activates the transfer of fatty acids, and esterfies cholesterol
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LPL hydrolyzes what from chylomicrons to place into adipose tissue
Fatty acids
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What does lecithin cholesterol acyl transferase LCAT do
It esterfies cholesterol in HDL
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Cholesterol is always stored how
As Cholestryl ester (esterfied cholesterol)
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Hepatic lipase
Further removes fats from IDL to create an LDL particle for binding, and participates in conversion of HDL2 to HDL3
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Apo is structurally homologous to what, and why is that significant
Plasminogen, it is believed that elevated lipoprotein (containing Apo's) slows down the breakdown of clots because it competes with plasminogen
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What is the importance of T3
T3 stimulates the breakdown of cholesterol and increases the number of LDL receptors, therefore increasing the rate of lipolysis.
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What substances inhibit the synthesis of intracellular cholesterol
- "GC SLiM"
- Glucagon
- Cortisol
- Simvastatin
- Lovastatin
- Mevastatin
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What are the steps to making intracellular cholesterol
- Acetyl-CoA
- HMG-CoA
- Mevalonate
- Intracellular cholesterol
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What are the stages of plaque formation in the arteries
- Endothelial injury in vessel by oxidized LDL
- Monocytes migrate to site, become macrophages
- Macrophages become foam cells by consuming oxidized lipoproteins
- Foam cells release growth factors and cytokines
- Smooth muscle cells migrate from media triggered by cytokines and growth factors
- Smooth muscle cells proliferate producing collagen, taking up lipids, and making foam cells
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Weight gain has what effect on plasma lipids
Decrease HDL, increase VLDL
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Hypothyroidism effects what plasma lipid
Increase in LDL by decreasing T3 receptors
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What does type I inherited hyperlipoproteinemia effect and how is it treated
- Deficiency in LPL and C-II
- Epigastric pain and turbid retina
- Treat with low fat, high carb diet, and Gemifibrozil
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What does type IIa inherited hyperlipoproteinemia effect, and how is it treated
- 4 classes of LDL receptors become defective
- Coronary heart disease and plaques result
- Treat with Statin or Resin
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What does type III inherited hyperlipoproteinemia effect
- Apo E2
- Causes Xanthomas, coronary heart disease and plaques
- Treat with Niacin, Statin, or Gemfibrozil
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What does type IV inherited hyperlipoproteinemia effect
- "4 diabetes hit the door!"
- Elevated VLDL associated with glucose and high insulin
- Treat with Niacin, Gemfibrozil
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What does type IIb inherited hyperlipoproteinemia effect
- "2b most risky"
- This is the most common
- Increased LDL delayed clearance of VLDL
- High risk of coronary heart disease
- Treat with Niacin, or Statin
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Xanthelasmas
Mole like collection of cholesterol usually around eyes, indicate hypercholesterolaemia in younger individuals
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Eruptive xanthomas
Collection of cholesterol around body as bumps, common in older people with hypertriglyceridaemia
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Arcus sinilus
White ring around the iris of the eye, often seen in hypercholesterolaemia
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