Lipoprotein metabolism

How are simple, unesterified fatty acids transported?

Bound to proteins in the blood, bound to serum albumin

How are complex fatty acids transported in the blood?

As lipoproteins

What fats are transported as lipoproteins?

Phospholipids, triacylglycerol, cholesterol, and cholesterol esters

What is the function of lipoproteins?

Transport of neutral, insoluble lipids

What is the structure of lipoproteins?

Hydrophobic core surrounded by a phospholipid micelle.
Integral apoproteins (Apo B), and peripheral apoproteins (Apo C)

How many types of lipoproteins are there?

6

What are the types of lipoproteins?

Chylomicrons (CM).
Chylomicron remnants (CM remnants).
Very low density lipoproteins (VLDL).
Intermediate density lipoproteins (IDL).
Low density lipoproteins (LDL).
High density lipoproteins (HDL)

How do the properties of lipoproteins change from CMs to HDLs?

Diameter decreases, density increases.
% protein increases, % lipid decreases

How does the amount of TAG, phospholipids, CE, cholesterol and FFAs change from CMs to HDLs?

% TAG decreases.
% phospholipids increases.
% cholesteryl ester increases.
% cholesterol increases.
% FFA increases

What are the classes of Apoprotein?

Apo A-I and A-II.
Apo B-48 and B-100.
Apo C-I to III.
Apo D.
Apo E

What are the three main families of apoprotein?

Apo B-48 family: CM and CM remnants.
Apo B-100: VLDL, IDL, LDL.
Apo A: HDL species

How are Apo B proteins coded?

Apo B-48 is a truncated version of Apo B-100. Apo B-100 is cleaved at Gln-2153.

Where is Apo B-48 produced?

In the intestine.
Synthesis is controlled by tissue specific expression of apo-B mRNA editing enzyme

How are dietary triacylglycerides taken into the body?

Converted to FFAs and monoacylglycerides, then transported across the lipid bilayer and converted back to TAGs.
TAG and other lipids and proteins form chylomicrons

How are chylomicrons absorbed?

Interact with lipoprotein lipase, Cm converted to FFAs and CM renmants

What is Apo C-II?

79 amino acid protein expressed in the intestine and liver.

How is the transcription of Apo C-II activated?

Activated by FXR/RXR

What is the function of the N and C terminal domains of Apo C-II?

N-terminal domain involved in lipid binding.
C-terminal domain activated lipoprotein lipase

Where is LPL found?

Surface of endothelial cells of capillaries. Attached to GAG.

How are CM remnants absorbed?

Enter hepatocytes via remnant receptors.
Apo E recognised by remnant receptor.

What types of remnant receptor are involved in CM remnant absorption?

LDL receptor (LDLR), LDL related protein (LRP), heparin sulphate proteoglycan (HSPG)

How are endogenous lipids produced?

Excess carbohydrates and lipids are converted into triglycerides.

Where are VLDLs synthesised?

In the liver

Where are the apoproteins for VLDL synthesis produced?

In the ER.
Lipids transferred to protein by microsomal triglyceride transfer protein (MTP)

Where are pre-lipoprotein particles assembled?

Golgi

What occurs to VLDLs once they have been produced?

Converted to FFAs and IDL by lipoprotein lipase

What occurs to IDLs?

40% converted to LDLs by loss of fatty acids.
60% taken up by hepatocytes through LDL receptors

How are IDLs converted to LDLs?

By hepatic lipase or CEPT.

How are IDLs recognised by LDL receptors?

Recognises Apo B-100 and Apo E

What happens to LDLs?

Taken up by peripheral tissues or liver

What is the main role of LDLs?

Transport of hepatic cholesterol to peripheral tissues

What is the structure of the LDL receptor?

Ligand binding domain, EGF precursor homology region, O-linked sugars, membrane spanning region, and a cytoplasmic region

What amino acid is important in the correct folding of the LDL receptor?

Cysteine

What Apo proteins are recognised by the LDL receptor?

Apo B and Apo E, Apo E has a much higher affinity

What is the function of the EGF precursor homology domain in the LDL receptor?

Helps to link the hydrophilic and hydrophobic regions of the receptor

What is the function of the O-linked sugar region in the LDL receptor?

Joins the membrane and cytoplasmic regions of the receptor

Where are the N and C terminal of the LDL receptor found?

N-terminal=Extracellular.
C-terminal=In the cytoplasm

How is the LDL receptor inserted into the membrane?

Synthesised in ER and transported from Golgi in a vesicle to the membrane.

How does an LDL particle enter a cell?

Binds to LDL receptor due to recognition of Apo proteins.
Coated pit forms to allow the integration of cholesterol into the cell, forms an endosome containing the LDL and LDL receptor

What happens to the endosome containing LDL and the LDL receptor once it is internalised?

Receptor recycled back to the membrane.
Protein lysed into amino acids.
Cholesterol present forms a droplet which is transported to the ER

What is the affect of cholesterol in the cell?

Decreases LDL receptor and HMG-CoA reductase synthesis

What can class A scavenger receptors bind to?

Bind charge modified and oxidised LDL

What can class B scavenger receptors bind to?

Bind charge modified, oxidised, and normal LDL

What can be taken up by scavenger receptor B1?

Acts as a HDL receptor for selective cholesteryl ester uptake by the liver

What is the function of reverse cholesterol transport (RTC)

Peripheral cell cholesterol is returned to the liver

What HDL species are involved in reverse cholesterol transport?

Pre β HDL, HDL 3, HDL 2

Pre β HDL (Apo AI, Apo AII, Phospholipids, cholesterol).

What is found in Pre β HDL?

Apo AI, Apo AII, Phospholipids, cholesterol.
Disc shaped

What is found in HDL 3?

Cholesterol becomes esterified.
Spherical

What is found in HDL 2?

Cholesteryl ester and triglycerides

How is pre β HDL converted to HDL 3?

By the action of lecithin cholesterol acyl transferase (LCAT)

What transporter is involved in the transport of cholesterol and lipoprotein containing vesicles?

ABCA1, transports vesicles produced in the Golgi out of the cell.
Vesicles then associates with Apo AI and Apo AII

What is the structure of the ABCA1 transported?

Two domains linked by a region domain.
Each domain has a cytosolic ATP binding region (NDB)

Why do spherical vesicles form once cholesterol is esterified?

Increased hydrophobicity of cholesteryl ester compared to cholesterol causes spherical structure

What is the structure of ApoA-1?

243 amino acids, molecular weight of 29 kDa

What are the functions of ApoA-1?

Transfer of cholesterol from peripheral cells to discoidal HDL, activation of LCAT

How is ApoA-1 arranged in disc shaped HDL particles?

2 ApoA-1 molecules arranged in anti-parallel double-belt structure.
Solvent exposed loops interact with LCAT

How can the molecules in VLDLs and HDL3 be transferred?

Triglycerides from VLDL can move to HDL3.
Cholesterol from HDL3 can move to VLDL.
Catalysed by Cholesterol ester transfer protein (CETP)

How can cholesterol in HDL be returned to the liver?

Selective uptake of cholesteryl ester via scavenger receptor B1, produces lipid poor A-1 which is transported to non-hepatic tissues

What properties do scavenger receptor B1 (SRB1) have?

High affinity for HDL, mediate selective uptake of CE from HDL core without internalisation of the particle