Oxidized LDL and the metabolic syndrome

Abstract

The metabolic syndrome is a common and complex disorder combining obesity, dyslipidemia, hypertension and insulin resistance. It is associated with a high cardiovascular risk that can only partially be explained by its components. There is evidence that low-grade inflammation and high oxidative stress add to this risk. Oxidized LDL, a marker of lipoprotein-associated oxidative stress, is an emerging cardiovascular risk factor. In this review, we demonstrate that the metabolic syndrome exacerbates oxidized LDL in a feedback loop. We introduce molecular mechanisms underlying this loop. Finally, we demonstrate that weight loss and statin treatment lower metabolic syndrome factors associated with a reduction of oxidized LDL. The current data warrant further investigation into the role of lifestyle and therapeutic interventions that inhibit tissue-associated oxidation of LDL in the prevention of the metabolic syndrome.

Figures

Figure 1. Effects of weight loss in obese mice

Mice deficient in both the LDL receptor and the leptin gene feature most of the metabolic syndrome components associated with increased oxidative stress and inflammation and, thereby, with accelerated atherogenesis and loss of left ventricle function. Weight loss is associated with an improvement of the metabolic profile associated with inhibition of atherogenesis, increase of plaque stability and improved left ventricle function. Our observations in obese mice are relevant for humans. Indeed, the metabolic syndrome is associated with higher cardiovascular risk, and weight loss decreases this risk.

Figure 2. Common effects of weight loss and rosuvastatin treatment in obese mice

In the aortic arch, we identified PPAR-γ as a regulator of oxidative stress and inflammation. Induction of PPAR-γ results in an increase of SOD1 that is associated with a reduction of the oxidation of LDL by decreasing reactive oxygen species. Induction of PPAR-γ is also associated with increased expression of CD36, resulting in increased uptake of oxidized LDL. The reduction of plaque-oxidized LDL results in an increased PPAR-γ expression that, through LXR, induces the expression of ABCA-1. This is crucial for the efflux of inflammatory lipids, which tend to reduce PPAR-γ expression, out of the plaque. Arrows indicate activation and flat ends indicate inhibition. ABCA-1: ATP-binding cassette, subfamily A member 1; LXR: Liver X receptor; PPAR: Peroxisome proliferator-activated receptor; SOD: Superoxide dismutase.

Figure 3. Configuration of the 4E6 sandwich-type and competition ELISA

The sandwich-type ELISA uses ox-LDL-specific monoclonal antibody 4E6 as the capturing antibody and the anti-ApoB100-specific antibody 8A2 as the tagging antibody. The latter is conjugated with HRP, which reacts with a specific substrate to yield a yellow-colored reaction product; this is quantified in the spectrophotometer. The competition ELISA requires preincubation of the plasma sample with 4E6. The sample is then applied to a microtiter plate, on which in vitro ox-LDL is immobilized. There, the ox-LDL in the plasma and the in vitro ox-LDL compete for 4E6. After washing, 4E6 bound to the immobilized ox-LDL is detected with HRP conjugated rabbit-anti-mouse antibodies. The reaction is completed as in the sandwich-type ELISA. HRP: Horseradish peroxidase; ox-LDL: Oxidized LDL.

Figure 4. Mechanisms of oxidation of LDL

Several cell types and cell-mediated enzymatic reactions can lead to the oxidation of LDL. The common process is the formation of aldehydes, which interact with lysine residues in the ApoB100 protein in LDL. The antibody 4E6 is directed against a conformational epitope generated by this interaction. Interestingly, not only cells in the vessel wall, but also cells in adipose tissues, mediate oxidation reactions. Arrows indicate activation and flat ends indicate inhibition. HOCL: Hypochlorous acid; NO: Nitric oxide; ox-LDL: Oxidized LDL; PUFA: Polyunsaturated fatty acid.

Figure 5. Prevalence of cardiovascular disease according to the presence of the metabolic syndrome and high oxidized LDL

As expected, the metabolic syndrome was associated with a higher odds ratio for cardiovascular disease. In agreement with our earlier studies, high ox-LDL was associated with a higher prevalence. The highest prevalence was observed in persons with the metabolic syndrome and high ox-LDL. In the left panel, absolute levels of ox-LDL (expressed in mg/dl) were used. In the right panel, the ox-LDL-to-LDL-cholesterol ratios were used. Data are from the Health ABC study [56]. CVD: Cardiovascular disease; MS: Metabolic syndrome; OR: Odds ratio; ox-LDL: Oxidized LDL.

Figure 6. Elevated oxidized LDL is associated with a high risk of the metabolic syndrome

The data are odds ratios (and 95% CI intervals) for incident metabolic syndrome after 5 years' follow-up in the second to fifth quintiles compared with the lowest quintile of oxidized LDL or LDL-cholesterol. These ratios were adjusted for age, gender, race, study center, cigarette smoking, BMI, physical activity and LDL-cholesterol or oxidized LDL. Data are from the Cardiovascular Risk Development in Young Adults (CARDIA) study [65].