Electronegative LDL from Rabbits Fed with Atherogenic Diet Is Highly Proinflammatory

Area of Science:

• Cardiovascular Biology
• Immunology
• Lipid Metabolism

Background:

• Electronegative low-density lipoprotein (LDL(-)) is associated with cardiovascular diseases like atherosclerosis.
• The role of LDL(-) in atherosclerosis-related inflammation remains incompletely understood.
• Diet-induced hypercholesterolemia may influence the inflammatory potential of LDL.

Purpose of the Study:

• To investigate the inducibility of LDL(-) by an atherogenic diet in rabbits.
• To explore the proinflammatory effects of diet-induced LDL(-) in macrophages.
• To elucidate the molecular pathways involved in LDL(-)-mediated inflammation.

Main Methods:

• Rabbits were fed an atherogenic diet, and LDL was isolated and fractionated into native LDL (nLDL) and LDL(-).
• LDL and oxidized LDL (ox-LDL) variants were incubated with THP-1-derived macrophages.
• Inflammatory markers (cytokines, signaling proteins) were measured using ELISA and Western blotting; receptor knockdown and pathway inhibition were employed.

Main Results:

• Diet-induced LDL(-) significantly upregulated pro-inflammatory cytokines (IL-1β, IL-6, TNF-α) in macrophages.
• LDL(-) increased the activation of key inflammatory signaling pathways, including NF-κB and MAPK (p38, JNK, ERK).
• LDL(-)-induced inflammation was dependent on LOX-1 receptor expression and signaling through NF-κB and ERK1/2 pathways.

Conclusions:

• An atherogenic diet promotes the production of a highly proinflammatory LDL(-) in rabbits.
• Diet-induced LDL(-) is a potent activator of inflammatory responses in macrophages via LOX-1, NF-κB, and ERK1/2.
• This study establishes a novel connection between diet-induced hypercholesterolemia and inflammation, mediated by LDL(-).