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45 Cards in this Set

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What are the most abundant lipids and their functions in the human body?
-Triglycerides: Major energy source for cells
-Phospholipids: Major component of cell membranes
-Cholesterol: Cell growth, cell division, membrane repair, steroid hormone production, bile salts, MAJORITY MADE IN THE LIVER
Where is the majority of cholesterol made?
In the liver
What are triglycerides?
3 fatty acids connected to glycerol via ester linkage

High density energy store
What are phospholipids?
2 fatty acids attached to a glycerol with a phosphate and polar head group
What are the sources, biosynthesis and degradation of cholesterol and cholesterol esters?
Diet: Only found in animal fat
Biosynthesis: Primarily in the liver from acetyl-CoA; (inhibited by LDL uptake)
Degradation: Only occurs in the liver
What is the precentage of fatty acids presents in FREE FORM and what are they derived from?
- Only 2-5% of fatty acid is present in FREE FORM (unesterified) - 95% are in the form of fatty acid esters

-Derived from:
*Intracellular hydrolysis of triglycerides in hepatic or adipose cells
*Lipoprotein lipase acting on circulating lipoproteins
How are FFA stored and mobilized during feed state and fasting?
-During feed state
*Insulin - inhibits hormone sensitive lipase and stimulates triglycerides synthesis, stimulates LPL
*Results in storage of triglycerides

-During Fasting:
*Drop in insulin activates HSL
*Triglycerides hydrolyzed in adipocytes
What are lipoproteins?
Lipids
Apolipoproteins
Lipids are insoluble
Lipoproteins transport lipids
Spherical soluble particle
What are apoproteins?
Proteins associated with lipoproteins
Functions:
-Structural
-Binding sites for receptors
-Activators or co-enzymes for lipid metabolism
*Direct the fate of lipoproteins
How are lipoproteins classified?
Based on buoyant density compared to physiological saline:
*Chylomicron and Chylomicron remnants
*VLDL - Very Low Density Lipoprotein
*IDL - Intermediate Density Lipoprotein
*LDL - Low Density Lipoprotein
*HDL - High Density Lipoprotein (GOOD)
What are the characteristics of the larger lipoprotein particles?
(Chylomicrons and VLDL)
-High content of triglycerides
-Lower density
What are the characteristics of the smaller lipoprotein particles?
(LDL and HDL)
-Less triglycerides
-Greater relative mass of protein
-Enriched in cholesterol esters
-Greater density
What are characteristics common among all lipoproteins?
-Protein content varies (number and kinds)
-Proteins can exchange
-Surface phospholipids and cholesterol can transfer
-Cholesterol esters and trigycerides need CETP (cholesterol ester transfer protein)
What are the exception in lipoproteins?
apoB 100 and B48 (structural)

Do not co-exist on the same particle
Only one apoB 100 or B48 molecule
Cannot exchange
What are the source, function and apoproteins in chylomicrons?
Source: Gut
Function: Transport of dietary TG
*FFA --> Adipose/muscle
*CE --> Liver via remnants
Apoproteins: B48, CII, E
What is the source, function and apoproteins in VLDL?
Source: Gut
Function: Transport of endogenously synthesized TG
*FFA --> Adipose/muscle
*CE --> LDL
Apoproteins: B100, CII, E
What is the source, function and apoproteins in LDL?
Source: Blood
Function: Delivers cholesterol to peripheral tissues
*CE to liver
*Peripheral Cells
Apoporoteins: B100
What is the source, function and apoproteins in HDL?
Source: Liver
Function: REVERSE CHOLESTEROL TRANSPORT
*Removes "used cholesterol from tissues
*Donates apolipoproteins to CM and VLDL
Apoproteins: A1, CII, E
What is the site of action and function of Apo A1?
Site of Action: Blood, plasma membrane

Function: Activates LCAT and CETP; binds to apo A1 receptors on cells requiring cholesterol extraction
What is the site of action and function of Apo B48?
Site of action: Gut

Function: Export of chylomicrons from intestinal cells
What is the site of action and function of Apo B100?
Site of Action: Various cells

Function: Ligand for LDL receptor; export of liver VLDL
What is the site of action and function of Apo CII?
Site of Action: Capillary walls

Function: Activates lipoprotein lipase
What is the site of action and function of Apo E?
Site of action: Liver

Function: Receptor ligand - clears remnants, IDL, and HDL
What are the similarities and differences between apoB100 and apoB48?
-Same gene
-ApoB48; 49% of apoB100 in size
-ApoB48 is produced exclusively by the intestine:
*result of tissue-specific expression of an mRNA-editing enzyme activity (editase)
*a substitution of thymidine (T) for cytidine (C) creates a premature stop codon
What are chylomicrons?
-largest of the lipoproteins
-Most triglyceride-rich
-Least dense
-Relatively short-lived
-Nearly absent in the fasting state
What are the characteristics of chylomicrons?
-Assembled in intestinal mucosal cells
-Enter the lymphatic system then blood via the thoracic duct
-Contain apoprotein B48; acquire other apoproteins from high density lipoproteins (HDL).
-TRANSPORT DIETARY TG:
*to the adipose tissue (storage)
*to muscles (for energy)
How are chylomicrons assembled?
-Size of particle depends on the amount of triglyceride available
-Enter secretory vesicles
-Picks up apo A, C and E in plasma
-TG composition closely resembles dietary intake
What do Very Low Density Lipoproteins (VLDL) contain and transport?
Contain:
-Nascent VLDL contain apo B100
-Contain mostly TG but with a significant amount of cholesterol and cholesterol ester

Transport:
-Endogenously synthesized TG to the extra hepatic tissues (storage or energy)
What are the characteristics of VLDLs?
-Large lipoproteins
-Triglyceride-rich particles
-Produced by the liver
-Acted upon by LPL to liberate FFA
-Lipolysis creates smaller, more cholesterol ester-rich VLDL remnants
-apoB100 as the major structural apoprotein
How are VLDLs assembled?
-Occurs in the liver:
*hepatocytes, uptake plasma lipoproteins
*hepatocytes secrete VLDL
-Three sources of the fatty acids
*plasma FFA that dissociate from albumin
*from triglyceride-rich lipoproteins that have undergone receptor-mediated endocytosis
*synthesized in the liver de novo
-ER/Golgi same as for chylomicrons
-particles enter secretory vesicles for release in the space of Disse
What are Intermediate-density lipoproteins (IDLs)?
-50% of small VLDL are lipolytically converted to IDL
-Contain apoB100
-Enriched in cholesterol esters
What are the characteristics of low-density lipoproteins (LDLs)?
-Cholesterol-rich
-95% of protein is apoB100
-70% of the cholesterol in plasma
-From lipolysis of VLDL
-Deliver cholesterol to extra hepatic tissue***
-High level of plasma LDL or apoB100 is the best single predictor of increased risk for atherosclerosis
How are IDLs and LDLs formed?
-50% of small VLDL are converted to IDL and LDL
-Are VLDL remnants!!!!*****
-Delipidation:
*Become depleted in triglycerides
*Become enriched in cholesterol esters
What are the 3 pathways of lipoprotein metabolism?
1. Exogenous/chylomicron pathway (dietary fat)
2. Endogenous pathway (lipids synthesized by the liver)
3. HDL metabolism (apoproteins transfer, cholesteryl ester transfer, REVERSE CHOLESTEROL TRANSPORT)
What is the site of action, activator and function of Lipoprotein lipase (LPL)?
Site of action: capillary walls

Activator: apo CII

Function: excises FFA from TAGs in chylomicrons and VLDLs for adipose and muscle
What are the functions of HDLs?
-HDL carries "used" cholesterol back to the liver
-Donates some CE to circulating VLDL for redistribution to tissues
-HDL taken up by liver and degraded
-Cholesterol is excreted as bile salts or repackaged in VLDL
-Cholesterol synthesis in the liver is regulated by the cholesterol arriving through HDL (and dietary cholesterol returned by chylomicron remnants).
How do statins influence HDL and LDL levels?
HDL: raised

LDL: Lowered
How are lipoproteins cleared?
-irreversible removal from plasma
-relatively rapid
-Plasma half life:
*Large VLDL - minutes
*Small VLDL and IDL - 1-2 hours
*LDL - 2-3 days (loss of apoE; loss of affinity for LDL receptors); allows to gain access to tissues

-Enrichment of apoE is important - increases affinity for lipoprotein receptors
How is LDL cleared?
-40% of plasma LDL is cleared by the liver
-60% of plasma LDL is cleared by extrahepatic tissues
-LDL cholesterol is preferentially used (as opposed to de novo cholesterol syn.)
-70% of LDL clearance is mediated by LDL receptorsl remainder by scavenger receptors
What is the LDL Receptor Pathway?
-Found in clathrin coated pits (endocytosis)
-Receptor is recycled
-The LDL is degraded releasing lipid cargo
-Cholesterol uptake down regulates the cells own production of cholesterol and down regulates LDL receptor synthesis
-Mutations in LDL receptors causes increased plasma LDL levels (ie increased cholesterol levels) accelerates progress of athersclerosis (Familial hyperlipedimias)
What is corneal arcus?
Associated with hyperlipoproteinemia types 2 and 3. In males <40 yrs, predictive of increased risk of coronary artery disease
Where is tendon xanthoma found?
Found in type 2a hyperlipoproteinemia
What are the mechanisms of Atherogenesis?
-accumulation of lipoprotein due to shif of equilibrium
-Common cause of accelerated atherosclerosis is a deficiency of LDL receptors
-Inherited defect or high cholesterol, high saturated fat diet
What occurs as a result of the formation of oxidized LDL?
1. Uptake of oxidized LDL by "scaventer receptors" on macrophages that invade artery walls

2. Elicits CE deposition in artery walls

3. Atherosclerosis/CAD can develop
How is arterial plaque formed?
-Oxidized LDL stimulates endothelial cells, releasing chemokins and cytokines
*recruits monocytes into the arterial wall
-macrophages become enlarged and full of lipid: foam cells
-Foam cells form the "fatty streak", part of the atherogenic plaque
-Elevated LDL
*Increased residence time in plasma
*Increased modification/oxidation of LDL