13 - Lipoprotein Metabolism Flashcards
What are apolipoproteins? Describe the structure of lipoproteins
Emulsifying agents, proteins that bind with lipids to form lipoproteins (for structure, enzyme cofactors and ligands for receptors)
Lipoproteins are spherical complexes of lipids and proteins (phospholipid monolayer, unesterified cholesterol and mostly phosphatidylcholines)
Apolipoproteins are on the surface and TAG and cholesterol esters are sequestered in the central core
How do the following methods isolate lipoproteins based on their composition?
- Ultracentrifuge
- Chromatography
- Electrophoresis
- Ultracentrifuge: density
- Chromatography: size
- Electrophoresis: protein charge/composition and size
Eg. with more lipid (TG) the lipoprotein will be least dense and will float (move to top of ultracentrifuge), or lag in chromatography or electrophoresis (maybe)
List the four main types of lipoproteins that can be found and the amount of homogeneity of each one
Chylomicron: intestinal, heterogenous and biggest, most TG
VLDL: Heterogenous
LDL: More homogenous
HDL: most homogenous and smallest, least TG
What is the function of apolipoprotein A-I?
Activates LCAT (lecithin-cholesterol acyltransferase)
On chylomicrons and HDL
What is the function of apolipoprotein B-48?
Cholesterol clearance
On chylomicrons only
What is the function of apolipoprotein B-100?
Cholesterol clearance
On VLDL, IDL, LDL (only apolipoprotein on LDL)
What are the two broad classes of apolipoproteins?
- Based on their ability to exchange between lipoprotein particles (related to aqueous solubility of the protein)
ApoB proteins are non-exchangeable; all of the remaining apolipoproteins are exchangeable.
Exchangeable apolipoprotein structure and function is explained by the amphipathic alpha helix model (one side is hydrophilic and the other hydrophobic).
How are lipoproteins assembled?
- mRNA is transcribed on rough ER, peptide has signal peptide attached.
- Glycosylation of peptide occurs with lipid synthesis in SER and the lipid is bound inside the apolipoprotein
- The particle is sent through golgi where it receives terminal glycosylation before being secreted as a secretory vesicle
- It fuses with the plasma membrane to receive post secretory modifications
What happens if you have dysregulation in ApoE?
Accumulation in IDL
IDL is the product of VLDLs after they have deposited free fatty acids into adipose tissue or muscles. OR products of HDL after conversion from plasma LCAT (lecithin-cholesterol acyltransferase)
They are cleared at the liver after becoming LDLs
Describe the fate of dietary fat through the circulatory system
Exogenous pathway
- Entrapped in chylomicrons at intestine
- Lipoprotein lipase liberates some TG as FA to leave remnants which are taken up into the liver by hepatic lipase, where the dietary cholesterol is processed
Endogenous pathway
- Liver secretes VLDL from the dietary cholesterol
- These deposit more FAs in adipose tissue/muscle, leaving IDL
- IDL are converted to LDL and cleared at the liver or in extrahepatic tissue
- Extrahepatic tissue makes HDL which may be converted into IDL
Why is glycerol transferred to the serum from chylomicrons, other than adipose and/or muscle tissue (like TG are)?
Adipose tissue and muscle cannot phosphorylate glycerol, has to be picked up by the liver or kidney from the serum.
Hydrolysis of TAG on chylomicrons by lipoprotein lipase is dependent on what?
Presence of apoCII (acquired from HDL by exchange)
Loss of apoCII and apoCIII exposes apoE for receptor mediated uptake of the remnant
Describe the synthesis and actions of lipoprotein lipase
Describe deficiency of LPL
- Synthesized by adipocyte and transported to surface where it is anchored by heparan sulfate
- LPL binds to Apo-CII on chylomicron surface (from HDL exchange)
- Deficiency of either LPL or apoCII means that chylomicrons cannot be metabolized and accumulate in the blood
Describe VLDL metabolism
- VLDLs made in golgi of liver
- ApoC and ApoE are transferred from HDL
- FA from TAG are hydrolyzed by lipoprotein lipase found in adipose, aorta, heart, spleen (etc. - non-hepatic tissue)
- As the TAG is removed from the VLDL, the particle becomes smaller and becomes an IDL
- Further loss of TAG and it becomes a LDL (by hepatic lipase)
- LDL are taken up by B-100 receptors found in the liver and non-hepatic tissue
Describe three mechanisms for the accumulation of cholesterol from LDL
- Activation of ACAT leading to esterification
- Inhibition of HMGCoA reductase to decrease cell cholesterol synthesis
- Inhibition of synthesis of more LDL receptors
