**3.1 Changes in lipid composition of LDL particles and primary structure of apoB-100**

At present, more research is placed on the effects of oxidation and glycosylation on LDL.

LDL oxidation: when circulating LDL is out of extremely high levels, oxidized LDL (ox-LDL) is rarely found in circulation due to the presence of plasma antioxidants and vitamin C. In this case, the oxidation of LDL occurs mainly in the arterial wall. Vascular wall cells (endothelial cells, smooth muscle cells, and macrophages), stimulated by the attack factors, produce and release a large number of reactive oxygen species (ROS) and reactive nitrogen species (RNS). Free radicals rapidly oxidize the polyunsaturated fatty acids (PUFAs) on the surface of LDL into fatty acid fragments [10, 11]. This modification is produced in the surface of the LDL particles, so the physical and chemical properties of LDL change little. We call this LDL the "minimum modified LDL," which retains the affinity for the LDL receptor. Then the "minimum modified LDL" activates the endothelial anti-apoptosis signaling pathway, induces endothelial cells to express tissue factors and chemokines, promotes the aggregation of inflammatory cells, triggers an inflammatory reaction, generates a large number of free radicals, and leads to the continuous oxidation of LDL. Continuous oxidation further converts fatty acid fragments into aldehydes**,** and aldehydes interact with the lysine residues of apoB-100 to form new antigenic determinants, inducing the formation of autoantibodies [12, 13]. After complete oxidation, ox-LDL completely loses its affinity to LDLR and binds specifically to the scavenger receptors (SRs) [14].

With an extremely high level of circulating LDL, the antioxidants in the body are insufficient to maintain the antioxidant protection of nLDL. And nLDL oxidizes rapidly even without strong attack factors. Meanwhile, high levels of LDL, in turn, promote the binding of NO with hydrogen peroxide to produce peroxynitrite (ONOO-), which is a strong oxidant and constantly attacks endothelial cells, resulting in endothelial dysfunction [15, 16].

LDL glycosylation: LDL glycosylation is a nonenzymatic reaction, and the reaction rate depends on the level of glucose and the duration of exposure [17]. The 67th amino acid region of the N-terminus of apoB-100 is the main site of glycosylation and also the attachment site of LDLR. Glycosylation at this site reduces the affinity of LDL to LDLR, promotes the uptake of LDL by SRs on the surface of macrophages, and induces the formation of foam cells. Glycosylation of LDL enhances the susceptibility to further oxidation of LDL. In addition, the glycosylation process is accompanied by the production of free radicals, which often result in the simultaneous existence of LDL glycosylation and LDL oxidation [18]. This is among the causes of peripheral vascular disease in patients with advanced diabetes.
