Lipoprotein Types and Transport

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Lipoprotein Types and Transport
Lipoproteins
What are lipoproteins and why do we need them?
Lipoproteins are a handful of different molecules that interact with water insoluble fat molecules, and transports those fats in the plasma
The textbook describes the lipoproteins as “oil tankers”
 Different lipoproteins are responsible for the transportation of different fats
Lipoproteins allow fat to be dissolved into the plasma
Transport lipids in plasma by the protein portion (keep lipids soluble)
Transporting their lipid content to & from tissues
N.B. In humans, the transport system is less perfect than in other animals cholesterol deposition in tissues atherosclerosis 
Lipoprotein function
Composition of Plasma Lipoproteins
Neutral core (TAG, exogenous or de novo, cholesterol esters)
Amphipathic apolipoprotein
Phospholipids
Cholesterol
Transport of cholesterol and lipoprotein
Lipoprotein
Chylomicron 
Transpot TAG
Cholesterol
From diet
VLDL, LDL, HDL 
Transpot TAG
Cholesterol
From liver
Cholesterol
Found only in animals
Important component of membranes, steroid hormones, bile and Vitamin D
Exogeneous cholesterol comes from diet
Endogeneous cholesterol is synthesized by the liver
70 % of cholesterol associated with cellular components
30 % is in the plasma ( ⅓ free form , ⅔ esterfied )
 
Transported by HDL and LDL
Apoliproproteins
Outer protein “shell” of the lipoprotein molecule
The protein – lipid interaction allows the water insoluble lipid to become soluble in plasma
The apolipoprotein is responsible for the interactions with cell membranes and enzymes to transport lipids to specific locations
Apolipoproteins
ApoA-I, II and IV
ApoB-48 and 100
ApoC-I, II and III
ApoD
Cholesterol ester transfer protein
ApoE
ApoH
Apolipoproteins
Apolipoprotein A-I
ApoA-I synthesized in intestine and liver
Associated with chylomicrons and HDL
Apolipoprotein A-II
Exchangeable apolipoprotein
Associated with HDL
ApoA-I and II bind to HDL
HDL, highest density lipoprotein due to it’s protein lipid ratio
Contains almost no cholesterol or cholesterol esters when synthesized
Obtains cholesterol esters from cholesterol by the HDL associated enzyme, lecithin: cholesterol acyltransferase (LCAT)
LCAT
LCAT is synthesized in the liver 
LCAT makes cholesterol esters from free cholesterol found in chylomicron remnants and VLDL remnants 
LCAT transfers a fatty acid from the C-2 position of lecithin to the C-3-OH of cholesterol, generating a cholesterol ester and lysolecithin 
The action of LCAT requires interaction with ApoA-I
Lipoprotein Types and Transport
 Function: Transport of fat soluble substances
 Types:	1) Chylomicron
2) VLDL
3) LDL
4) HDL
Chylomicrons
Made by: the small intestines in the fed state
Absorbed into: the lymph vessels, then --> 		moves into the blood
Rich in: TAGs
Function: deliver energy-rich triacylglycerol (TAG) to cells in the body cells to be used as fuel
Chylomicron
Triglycerides
	3 Fatty Acids					Glycerol
Adipose	Skeletal	Heart		 	 Blood
(storage)	Muscle		(energy)
		(energy)				 	 Liver
Chylomicron Remnant
Liver
VLDL
= Very Low Density Lipoprotein
Made in: the liver from excess dietary carbohydrate and protein along with the Chylomicron remnant
Secreted into: the bloodstream
Rich in: TGs - triacylglycerol
Function: Deliver TGs to body cells
Contains apo B100
Similar to Chylomicrons, but made by different tissues
TAG is stripped from chylomicrons and VLDL through the action of lipoprotein lipase, an enzyme that is found on the surface of endothelial cells. This enzyme digests the TAG to fatty acids and monoglycerides, which can then diffuse into the cell to be oxidized, or in the case of an adipose cell, to be re-synthesized into TAG and stored in the cell.
Notes: triacylglycerol
VLDL
Triglycerides
	
	
3 Fatty Acids				 Glycerol
Adipose	Skeletal	Heart		 	 Blood
(storage)	Muscle		(energy)
		(energy)				 	 								Liver
Once VLDL looses much of its TG’s it becomes LDL
LDL
= Low Density Lipoprotein
Made in: the Liver as VLDL
Arise from: VLDL once it has lost a lot of its TG’s
Secreted into: the bloodstream
Rich in: Cholesterol
Function: Deliver cholesterol to all body cells
LDL
As VLDL particles are stripped of triacylglycerol, they become more dense. These particles are remodeled at the liver and transformed into LDL. 
The function of LDL is to deliver cholesterol to cells, where it is used in membranes, or for the synthesis of steroid hormones (blue pathway). Cells take up cholesterol by receptor-mediated endocytosis. LDL binds to a specific LDL receptor and is internalized in an endocytic vesicle. Receptors are recycled to the cell surface, while hydrolysis in an endolysosome releases cholesterol for use in the cell.
HDL
= High Density Lipoprotein
Made in: the Liver and Small Intestine
Secreted into: the bloodstream
Function: Pick up cholesterol from body cells and take it back to the liver = “reverse cholesterol transport”
Potential to help reverse heart disease
NORMAL CHOLESTEROL METABOLISM
Key concepts: synthesis
Primary synthetic sites are extrahepatic, but liver is key regulator of homeostasis
Key concepts: absorption
Largest source is biliary secretion, not diet.
Normal absorption: 50%
For cholesterol to be absorbed it must:
undergo hydrolysis (de-esterification by esterases)
be incorporated into micelles
be taken up by cholesterol transporter
be re-esterified and incorporated into chylomicrons
NORMAL TRIGLYCERIDE METABOLISM
Key concepts: absorption
Triglyceride (i.e. energy) assimilation is key to the survival of the organism.
Dietary triglyceride must be hydrolyzed to fatty acids, mono-glycerides and glycerol prior to absorption.
Fatty acids must partition to micellar phase for absorption.
For transport, triglyceride must be reconstituted from glycerol and fatty acid and incorporated into chylomicrons. 
Triglicerides
Glycerol with 3 attached fatty acids
Exogenesis source : Dietary
Endogeneous : Liver and tissue storage
95 % of body fat is triglycerides
Energy source when plasma glucose is decreased
Triglyceride catabolism is regulated by lipase, epinephrine and cortisol
Triglycerides transported by Chylomicrons (exogeneous) and VLDL (endogenous)
THE NORMAL FAT-TRANSPORT TASKS
 Lipid in plasma
Cholesterol and phospholipids - represent 2/3 of the plasma lipid, - slower turnover than fatty acids
The major fat-transport tasks are movement of free fatty acids and fatty acid esters of glycerol (glycerides)
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Lipoprotein Top 10 - resume
Lipoproteins transport various lipids ( fats ) thru plasma to different locations
High relationship between specific lipoproteins and CAD
Apolioproteins are the protein “shells” that interact with lipids and allow them to be water soluble
HDL ( Good Cholesterol ) transports cholesterol away from tissues to the liver
LDL ( Bad Cholesterol ) transports cholesterol to the tissues from the liver
VLDL transports endogenous triglycerides from liver to tissues
Chylomicrons transport exogenous triglycerides from GI tract to liver
Accurate Lipoprotein testing requires a fasting specimen 
LDL is not directly measured , but calculated from the Friedwald Calculation
atherosclerosis
HDL and ApoA-I negatively correlated with atherosclerosis
ApoA-II positively correlated with atherosclerosis
Deposits of fat and cholesterol building up in lining of arteries
Atherosclerosis->cardiovascular heart disease
How HDL prevents Atherosclerosis
HDL transports cholesterol from peripheral tissues to liver for catabolism
LCAT converts cholesterol into cholesterol esters
ApoA-I needs to be bound to HDL to activate LCAT
Conclusion
HDL
ApoA-I
Activate LCAT
Helps prevent
 atherosclerosis
ApoA-I
ApoA-II
HDL
Does not activate
LCAT
Leads to higher
Levels of 
Atherosclerosis
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