Plasma Lipoproteins

A lot of this will be a recap of PHAR3303, which is alright with me, because it might make writing about this topic a bit less painful.

Overview of lipid metabolism

See previous post: Lipid and Lipoproteins: Structure, Function and Metabolism

The classes of lipids and lipoprotein

See previous post: Lipid and Lipoproteins: Structure, Function and Metabolism

The main types of lipids are fatty acids, glycerol, and cholesterol, all of which can be absorbed and used by cells. Fatty acids and glycerol can also become esterified to form triglycerides, and cholesterol can become esterified to form cholesterol ester. Triglycerides and cholesterol ester are storage forms that are good for transportation purposes, but they generally aren't usable by the cell.

Normal plasma cholesterol levels are <4mmol/L for total cholesterol, <2.5mmol/L for LDL cholesterol, and >1mmol/L for HDL cholesterol. The LDL/HDL ratio is usually less than 5.2. Normal plasma triglyceride levels are <1.5mmol/L.

The function of different apoproteins

I've covered most of these lipoproteins in an earlier post, but here's a quick overview anyway:

• Apo-AI: Found in HDL. Activates LCAT, which is necessary for reverse cholesterol transport.
• Apo-B100: Found in VLDL and LDL. Functions as a ligand for the LDL receptor.
• Apo-B48: Found in chylomicrons and chylomicron remnants. Similar to Apo-B100, but the receptor-binding domain is absent.
• Apo-CII: Found in HDL, chylomicrons, VLDL, and IDL. Acts as a cofactor for lipoprotein lipase, which breaks down triglycerides into fatty acids and glycerol.
• Apo-E: Found in HDL and HDL remnants. Like Apo-B100, it acts as a ligand for the LDL receptor.

Mechanisms of formation and metabolism of each class of lipoprotein

The main lipoproteins covered in this lecture were chylomicrons, which are synthesised in the enterocytes of the intestines, and VLDL, which is synthesised by hepatocytes in the liver. Chylomicrons and VLDL are synthesised in a similar fashion, so I'll discuss both of them at the same time.

After fatty acids and glycerol enter the cell, they reform to create triglycerides. At the same time, cholesterol is esterified in the endoplasmic reticulum via ACAT-2. Triglycerides and cholesterol ester are packaged into lipoproteins via microsomal transfer protein (MTP). The apoprotein ApoB-48 is added in the intestines (to make a chylomicron), but in the liver ApoB-100 is added instead (to form VLDL). Lipoproteins are transferred through the Golgi apparatus to the cell membrane. Chylomicrons are released into the lymph system as they are too large for capillaries, whereas VLDL is released directly into the circulation.

The LDL receptor pathway

LDL receptors are located in clathrin-coated pits of some cells. Once LDL binds, it is taken up into lysosomes, which break them down. Once free, the cholesterol from LDL begins to have some effects on the cell: it downregulates HMG CoA reductase (thus decreasing further synthesis of cholesterol by the cell), upregulates ACAT (thus increasing esterification and storage of cholesterol), and downregulates LDL receptors (thus decreasing further LDL uptake).