Question

LDL particles have a higher percent content of cholesterol esters than VLDL particles. Based on what you learned about the endogenous pathway describe, mechanistically, how LDL is generated and why LDL’s have higher CE content than VLDL’s. Also, please describe how the CE will be extracted from the LDL particle by tissues.

Answer 1

• Generation of low-density lipoproteins (LDLs) and very low density lipoproteins (VLDLs) -

VLDLs and LDLs are generated by the endogenous pathway for lipid metabolism. The major core lipids in VLDLs are triacylglycerols.These VLDLs are then hydrolyzed by lipoprotein lipase into Intermediate-density lipoprotein (IDL) or VLDL remnants, which are then cleared from circulation or in some cases integrated into an LDL.

LDLs contain cholesterol esters (CE) and (a small amount of) triglycerides in their core. LDLs are internalized by hepatic and non-hepatic tissues. In the hepatic tissues, LDLs are converted into bile acids and then secreted into the intestines, whereas in the non-hepatic tissues, LDLs are used in cell membrane synthesis, hormone production, or are stored.

• When VLDLs lose triglycerides by the action of lipoprotein lipase, they become smaller as fewer fat molecules are now present with the same protein shell. These form LDLs that are hence, smaller and denser than VLDLs and contain a higher proportion of cholesterol esters.
• CE are extracted from LDL particles in the following way-

The process of LDL uptake by tissues is called receptor-mediated endocytosis.

Apolipoprotein B-100 on the surface of an LDL particle bind to specific receptor protein located in specialized regions called coated pits in the plasma mebrane. These coated pits contain a specialized protein called clathrin. THis formas a receptor-LDL complex which is then internalized by the plasma mebrane by endocytosis, formaing endocytic vesicles. These vesicles further fuse with liposomes which contains degradative enzymes. The protein component of the LDL is hydrolyzed to free amino acids and the cholesterol esters in the LDL are hydrolyzed by a lysosomal acid lipase. The LDL receptor then returns back to the plasma membrane. The released unesterified cholesterol is then used for membrane biosynthesis or stored in the cells after re-esterification.