Ox-LDL metabolism

Taken from: http://ethesis.helsinki.fi/

2.2.6. Metabolism of oxidized LDL

Ox-LDL particles are taken up by so-called scavenger receptors (Fig. 3). In the liver, Kupffer cells are the main site for mediating the in vivo uptake of Ox-LDL from the circulation and might thus protect against circulating Ox-LDL (van Berkel et al. 1995). 

Increased LDL levels in plasma lead to an increase entry of LDL into the intima through the injured endothelium, resulting in accumulation of LDL in the intima. 

LDL in the artery wall can be oxidatively modified by all the major cells of the arterial wall, i.e. ECs, SMCs, monocytes/macrophages, and in cell-free system by transition metals, lipoxygenase, myeloperoxidase, and nitric oxide (NO). 

Ox-LDL is taken up by a family of scavenger-receptors (SR) on the surfaces of cells such as macrophages, platelets, and ECs. However, which part of the Ox-LDL particle is being recognized by scavenger receptors is not fully understood (Greaves et al. 1998).

Certainly, both the lipids and the protein are oxidized under the oxidative condition. It was shown that the modified apolipoproteins extracted from Ox-LDL particles were efficiently internalized and degraded by macrophage scavenger receptors (Parthasarathy et al. 1987), while the oxidized lipids extracted from Ox-LDL were also recognized by scavengers (Terpsta et al. 1998). 

During the oxidation of LDL, the PUFA are broken down to smaller fragments and become conjugated with the -amino groups of lysine residues. Therefore, Steinberg (1997b) proposed that the recognition of Ox-LDL by scavenger receptors appears to be due to the masking of lysine -amino groups and subsequent changes in protein charge and configuration. 

The SRs mediate the endocytosis of the Ox-LDL, where the process is not down regulated. Increasing uptake of Ox-LDL via scavenger receptors certainly promotes cholesteryl ester accumulation and conversion to lipid-droplet filled foam cell formation which is the hallmark of fatty streaks and atherosclerotic plaques. 

The SR activity on the macrophages exhibits a remarkable broad binding specificity (Goldstein et al. 1979, Brown and Goldstein 1983); they not only recognize Ox-LDL but also other chemically modified proteins such as acetyl LDL (Ac-LDL), methylated LDL, suggesting they are multiligand receptors. So far, there are more than six classes of SRs (10 types) that have been shown to be responsible for endocytosis of Ox-LDL (Krieger 1997). 

Figure 3. Scheme depicting the uptake of native and Ox-LDL by macrophage receptors (Steinberg 1997a).