Lipid Transport Flashcards
What is the structure of a lipoprotein?
Hydrophobic core with triglycerides, cholesteryl esters
Surrounded with single-layer membrane with charges on outside that interact with aq surroundings
Proteins embedded in surface membrane
What proteins are embedded in surface membrane of lipoproteins?
Apo-proteins - for structural support and for interactions with receptors and catalytic proteins
Describe the transport of lipids with albumin
Free fatty acids are released from adipose tissue followed by wave of ketones
Neither require special transport and just bind to hydrophobic pockets on albumin while ketone bodies dissolve readily in serum
Describe the transport of lipids with lipoproteins
Lipid transport from enterocytes and liver require lipoproteins.
Triglycerides/cholesterol are released by enterocytes and liver and are loaded into lipoproteins through hydrophobic interactions. Amphipathic FA are converted to hydrophobic TG, cholesterol esterified to cholesteryl esters.
TG and CE form the hydrophobic core of lipoproteins and are shielded from hydrophilic environment
How are lipids unloaded from the lipoprotein?
Hydrolysis of TG by lipoprotein lipase releases FA
Hydrolysis of Cholestryl esters by cholesterol esterase releases cholesterol
What are the three routes of lipoprotein lipid traffic?
- Distribution of dietary lipids via chylomicron
- Distribution of lipids made by the liver: VLDL -> IDL -> LDL
- Transport of cholesterol to the liver for excretion: HDL
What creates serum turbidity after a meal?
Chylomicrons. They are the largest lipoproteins
Describe the distribution of dietary lipids
Lipids absorbed by the diet are packed into chylomicrons by enterocytes.
Chylomicrons deliver TG to muscles for consumptions and adipose tissue for storage
Describe the distribution of lipids made in the liver
Liver synthesizes lipids in the fed state and packs them into very low density lipoproteins (VLDL)
VLDLs distribute lipids to muscles and adipose tissue and get smaller and denser, turning into intermediate density lipoproteins (IDL) and low density lipoproteins (LDL)
When are VLDLs made?
Synthesized during fasting state to be used in fed state
Describe the transport of cholesterol to the liver for excretion
Liver synthesizes empty high density lipoproteins (HDL) that absorb cholesterol from peripheral tissues and transport it back to the liver for excretion
What is the triglyceride and cholesterol content of lipoproteins?
Chylomicrons - mostly TG (99%)
VLDL - contain TG and some cholesterol (92% TG and 8% chol)
IDL - 85% TG, 15% chol
LDL - 80% TG, 20% chol
HDL - mostly cholesterol, 50% TG, 50% chol
What occurs with defects in lipoprotein synthesis?
Hypolipidemia
What occurs with defects in lipoprotein unloading?
Hyperlipidemia
What are characteristics of hyperlipidemia?
Elevated TG and/or cholesterol
Risk for cardiovascular disease
What is primary dyslipidemia?
Abnormal concentration of serum lipids. Congenital disorders caused by mutations in lipoprotein metabolism.
Most frequent cause of dyslipidemia in children and often dominant mode of inheritance where a parent is affected
What are apoproteins?
Proteins in the outer membrane of lipoproteins that support structure and regulate function of the lipoprotein
What are the apoproteins for structural support?
ApoB48 - in Chylomicrons
ApoB100 - in VLDL, IDL, LDL
ApoA - in HDL
Interact with receptors on the surface of target cells
ApoB100 and ApoB48 are encoded by same gene - variation created by RNA editing
What apoprotein regulates fatty acid release from lipoproteins?
ApoC-II
Activates lipoprotein lipase on endothelial cells
What apoprotein regulates cholesterol entry into lipoproteins?
ApoA
Activates Lecithin-Cholesterol Acyltransferase (LCAT) for esterification of cholesterol
What apoprotein helps with interaction with lipoprotein receptors?
ApoE
A ligand for LDL and scavenger clearance
Describe chylomicrons, their apoproteins, and their development
Synthesized in enterocytes and transport lipids from diet. They get smaller as they lose lipids and turn into chylomicron remnants
Apoproteins - ApoB48, ApoC-II, and ApoE
Describe VLDL, their apoproteins, and their development
Synthesized in liver and transports fat and cholesterol from metabolic overflow. Get smaller and heavier as they lose fat and pick up cholesterol, converting to IDL and LDL
Lose ApoCII and then ApoE during transition
Apoproteins - ApoB-100. ApoC-II, ApoE
Describe HDL, their apoproteins, and their development
Synthesized in liver. Transports cholesterol from body back to liver and get bigger and heavier as they pick up cholesterol. Distribute ApoE and ApoC-II
Apoproteins - ApoA, ApoC-II, ApoE
Describe Lipoprotein A, their apoproteins, and their development
Function is unclear but is associated with cardiovascular risk
Apoproteins - ApoA-S-S-ApoB100
Describe the maturation of chylomicrons
Chylomicrons transport lipids from enterocytes around body and begin as non-functional particles filled with TG from the diet
Structural support provided by ApoB-48
After release from enterocytes, chylomicrons obtain ApoC-II and ApoE from HDL
Chylomicrons shrink as they lose lipids (lipoprotein lipase action) and turn to remnants
Chylomicron remnants bind to liver receptors through ApoE interactions and are removed via endocytosis
What has to happen to TG before they can enter enterocytes?
TG has to be hydrolyzed by pancreatic lipase
Describe the maturation of VLDL
Liver produces VLDL for fat distribution. Made during fasting and used in fed state
VLDL begins as non-functional particle filled with lipids and cholesterol with structural support provided by ApoB-100
VLDL pick up ApoC-II and ApoE from HDL
Lose TG through lipoprotein lipase and gain cholesterol by transfer with HDL
Transitions to IDL as it loses ApoC-II along with most of its TGs. Becomes LDL as IDL accumulates cholesteryl esters and lose ApoE
LDL binds to LDL receptors to clear contents into cholesterol requiring cells
What occurs if LDL accumulates?
Surplus LDL either due to overproduction or insufficient clearance, get oxidized and taken up via scavenger receptors which leads to plaque formation in blood vessels
Describe maturation of HDLs
HDLs begin in liver as empty particles assembled with ApoA scaffold
Deliver ApoC-II and ApoE to maturing chylomicrons and VLDL. Extract cholesterol from membrane and move to liver for excretion
Cholesterol extraction from plasma membranes through ABCA1 and transfer to surface of HD: with lipoprotein collides with membrane
HDL exchanges cholesteryl esters with LDL through CETP
Esterification of cholesterol through LCAT moves cholesterol into HDL for transport to liver where it is converted to bile salt and excreted in feces through bile duct
What is secondary dyslipidemia?
Consequences of other metabolic disorders and disturbances
Most frequent cause of dyslipidemia in adults
Often caused by poor diet, diabetes, alcohol use
Fredrickson Phenotypes
Classify dyslipidemia. Incudes 5 classes and allows us to identify the defective component based on observed elevation of serum cholesterol and TG
Elevated lipid fraction clues to lipoprotein
How does a patient with Fredrickson IIa present?
High LDL
High cholesterol
Family history of hypercholesterlemia
Physical examination shows fatty deposits on Achilles tendons and knuckles
Labs shows elevated cholesterol and normal TG
What are possible reasons LDL is elevated in Fredrickson IIa?
LDL no binding to receptor - Familial hypercholesteremia (FH), most common primary dyslipidemia
ApoB-100 defective - Familial defective ApoB100 (FDB), 2nd most common. Phenocopy of FH - diagnosis is by detecting of mutation
Why does diabetes result in hyperlipidemia?
Metabolism permanently in fasting state so adipose tissue constantly releases FAs and so there are too many FAs in circulation
Liver takes up excess FAs and makes TG, assembles VLDL.
Diabetic dyslipidemia characterized by high serum TG
