Complement protein C1q recognizes enzymatically modified low-density lipoprotein through unesterified fatty acids...

Area of Science:

• Biochemistry
• Immunology
• Molecular Biology

Background:

• Enzymatically modified low-density lipoprotein (E-LDL) particles are recognized by C1q, initiating complement system activation.
• Previous studies identified E-LDL as a C1 activator, but the specific component recognized by C1q remained unknown.

Purpose of the Study:

• To identify the specific component(s) of E-LDL recognized by the C1q molecule.
• To elucidate the mechanism of C1 activation by E-LDL.

Main Methods:

• Enzymatic modification of low-density lipoprotein (LDL) using various proteases and cholesterol esterase.
• Lipid extraction and incorporation into model vesicles.
• C1 activation assays.
• Treatment with human serum albumin and methyl-beta-cyclodextrin.
• Electron microscopy for C1q-E-LDL interaction visualization.

Main Results:

• Cholesterol esterase treatment was crucial for C1 activation by E-LDL, generating unesterified cholesterol.
• The lipid fraction of E-LDL, specifically unesterified fatty acids, triggered C1 activation.
• Methyl-beta-cyclodextrin treatment, which reduced cholesterol and unesterified fatty acids, inhibited C1 activation.
• Linoleic acid incorporation into model vesicles induced C1q interaction and activation, enhanced by cholesterol.
• Electron microscopy confirmed C1q binding to E-LDL via its globular domains.

Conclusions:

• C1q binding to E-LDL involves the recognition of unesterified fatty acids generated by cholesterol esterase.
• The globular domain of C1q interacts with these fatty acids.
• These findings offer insights into the role of E-LDL in atherogenesis.