Receptor-mediated low density lipoprotein catabolism in man

Area of Science:

• Biochemistry
• Human Physiology
• Metabolic Research

Background:

• Human low-density lipoproteins (LDL) bind to specific receptors on cells.
• Chemical modification of apolipoprotein (apoLDL) with 1,2-cyclohexanedione blocks arginyl residues, inhibiting LDL binding.
• This inhibition provides a method to study the in vivo role of the LDL receptor pathway.

Purpose of the Study:

• To investigate the quantitative contribution of the LDL receptor pathway to LDL catabolism in humans.
• To compare receptor-mediated and receptor-independent LDL catabolism in normal and familial hypercholesterolemic subjects.

Main Methods:

• Plasma clearance rates of native 125I-LDL and 131I-cyclohexanedione-treated LDL were measured in human subjects.
• Fractional clearance rates were calculated to differentiate between receptor-mediated and receptor-independent catabolism.
• LDL catabolism was assessed in both normal and heterozygous familial hypercholesterolemic individuals.

Main Results:

• Chemical modification of LDL significantly reduced its fractional clearance rate in all subjects.
• Normal subjects cleared 11% of their plasma LDL pool via a receptor-independent pathway.
• In heterozygous familial hypercholesterolemia, receptor-independent catabolism accounted for a larger proportion of overall LDL clearance compared to receptor-mediated catabolism.

Conclusions:

• The specific LDL receptor mechanism is functional in vivo and plays a significant role in overall LDL catabolism.
• The LDL receptor pathway accounts for approximately 33% of LDL catabolism in normal individuals.
• In heterozygous familial hypercholesterolemia, the LDL receptor pathway accounts for approximately 16% of LDL catabolism, highlighting its reduced function.