Soluble LOX-1 is an emerging risk factor with potential relevance in cardiovascular and metabolic diseases. Accumulating evidence indicates that sLOX-1 levels are increased in obese women and can be reduced with weight loss in overweight men.(8
) This study sought to clarify the role of weight loss interventions by determining the effects of CR, with and without aerobic exercise training, on circulating sLOX-1 levels in abdominally obese postmenopausal women. Our results not only confirm that sLOX-1 levels are reduced after weight loss, but extend these findings to women. More importantly, our study indicates that the magnitude of change in sLOX-1 levels is not different among weight loss interventions of equal energy deficit, regardless of whether the weight loss is induced by CR alone or in conjunction with aerobic exercise.
We previously reported that sLOX-1 levels were higher in obese postmenopausal women compared to lean and overweight women.(8
) In addition, sLOX-1 levels were positively correlated with body weight, BMI, percent body fat, and trunk fat. Similarly, Nomata et al. found that in obese men higher sLOX-1 levels were associated with a higher body weight and BMI.(9
) In the present study, we also found a positive association with BMI, but sLOX-1 levels were not correlated with body weight or any measure of body composition or body fat distribution. In addition, although weight loss resulted in significant decreases in sLOX-1 levels, changes in sLOX-1 were not related to changes in body weight or body fat in our study population.
One of the novel findings of this study was that the addition of either moderate- or vigorous-intensity aerobic exercise training had no added benefit in reducing sLOX-1 levels when performed in conjunction with CR. This observation is supported by the lack of an association between changes in sLOX-1 and improvements in VO2 max with weight loss. The similar changes in sLOX-1 levels among groups may have been due to the fact that the weight loss interventions provided equal caloric deficits, and therefore equal amounts of weight loss. Another novel finding was that age and BMI at baseline were significant predictors of the change in sLOX-1 levels with weight loss. Most notably, with increasing levels of obesity, the reduction in sLOX-1 was attenuated 2- to 3-fold compared to overweight women. These findings are consistent with the idea that with both aging and obesity, the normal physiological responses to a weight loss intervention may become impaired.
LOX-1 is expressed in endothelial cells, smooth muscle cells, macrophages, and adipocytes.(1
) At the cell surface LOX-1 can be cleaved at the membrane proximal extracellular domain by serine proteases and released into the circulation as sLOX-1.(4
) While elevated levels of sLOX-1 in the blood may reflect increased expression of membrane-bound proteins and disease activity, only a few studies have actually examined its relationship with cardiovascular disease and its associated risk factors. Hayashida et al. was the first to report on circulating sLOX-1 levels in humans, demonstrating that serum levels were significantly increased in acute coronary syndromes.(5
) Other studies have reported that sLOX-1 levels are higher in diabetics and coronary artery disease (CAD) patients than healthy controls.(7
) Interestingly, circulating sLOX-1 levels were positively correlated with hemoglobin A1c and advanced glycation endproducts in diabetics, while in CAD patients sLOX-1 levels increased with increasing numbers of diseased vessels and higher levels of inflammation and oxidative stress.(6
) As described above, we and others have shown that higher sLOX-1 levels are also associated with a higher BMI and greater body weight and body fat.(8
) Thus, these findings support a relationship between sLOX-1 and inflammatory and metabolic diseases, and highlight its potential as an important cardiovascular disease risk factor in various populations.
Several studies show that in vascular cells LOX-1 expression is induced in vitro
by various pro-inflammatory, pro-oxidant and vasoactive stimuli, such as oxidized LDL, angiotensin II, and C-reactive protein, and is upregulated in vivo
by hyperlipidemia, hypertension, and diabetes.(2
) These data strongly support a pathophysiological role for LOX-1 in the development of cardiovascular disease. On the other hand, one study by Chui et al. found that treatment with the anti-diabetic drug rosiglitazone significantly increased LOX-1 expression in mouse 3T3-L1 adipocytes.(1
) In addition, they reported that LOX-1 mRNA levels in white adipose tissue are higher in ob/ob
mice compared to lean mice and are further increased by ciglitazone treatment. The authors suggested that adipose tissue could help to inhibit the formation of atherosclerotic lesions by removing oxidized LDL from the circulation. Alternatively, adipose tissue LOX-1 expression may be essential for the uptake of cholesterol required for normal cellular function; however, in excess, it could contribute to the development of obesity and insulin resistance. Taken together, these data suggest that the pathophysiological role of LOX-1 may be cell-specific and influenced by the presence of other risk factors. More studies are needed to better characterize the factors that regulate its expression in adipose and non-adipose tissues.
Little is known about the regulators of sLOX-1 expression. Our data show that weight loss can reduce sLOX-1 levels in overweight and obese women. In fact, 20 weeks of CR with and without aerobic exercise elicited a 14% reduction in body weight and a 23% reduction in sLOX-1 levels. Nomata et al. recently reported the effects of a 12-week weight reduction intervention on serum sLOX-1 levels in overweight middle-aged men.(9
) They found that sLOX-1 levels decreased 72% with a 10% reduction in body weight. While gender differences likely influence the magnitude of change in sLOX-1 levels with weight loss, these data indicate that clinically significant weight reduction is effective at lowering sLOX-1 levels in both men and women. In addition, although we did not find a correlation between reductions in body weight and sLOX-1 levels as was previously reported in men,(9
) both our results and the results of Nomata et al. suggest that changes in sLOX-1 with weight loss are associated with obesity-related factors. Mitsuoka et al. demonstrated that the inflammatory cytokine interleukin-18 (IL-18) stimulates the release of sLOX-1 in cultured cells, and IL-18 infusion significantly increases sLOX-1 levels in mice.(15
) Data from other studies indicate that diabetes-related factors, including glucose and advanced glycation endproducts stimulate the release of sLOX-1 in endothelial cells.(7
) In addition, sLOX-1 levels are reduced by 13% in diabetics after 6 months of glucose-lowering therapy.(7
) The reduction in sLOX-1 correlated with improvements in hemoglobin A1c levels and advanced glycation endproducts. Use of anti-hypertensive medications was also associated with lower sLOX-1 levels in these patients.(7
) Taken together, it appears that sLOX-1 levels are increased by pathological stimuli and can be reduced by various lifestyle therapies. Given that obesity is associated with a number of cardiometabolic risk factors, it is possible that improvements in inflammatory status, glucose homeostasis, and blood pressure may contribute to reductions in sLOX-1 levels in overweight and obese men and women.
In conclusion, we found that weight loss interventions of equal energy deficit have similar effects on sLOX-1 levels in overweight and obese postmenopausal women, regardless of whether they involve aerobic exercise training. The present study has several strengths including the highly controlled dietary intervention, the well-standardized exercise program, and the randomization of abdominally obese postmenopausal women, a population at high risk for cardiovascular disease. However, there are a few limitations to point out: 1) the use of a controlled diet may limit the applicability of the results to the general population; 2) the relatively short duration of the study limits our ability to predict the effect of long-term weight loss on changes in sLOX-1 levels; and 3) we cannot determine the exact source of the circulating sLOX-1 (i.e. vascular or adipose tissue). Future studies will need to determine whether increased expression of sLOX-1 is a cause or a consequence of obesity and its related metabolic abnormalities. More importantly, it will be necessary to identify the processes that regulate LOX-1 cleavage from the cell surface. Although its physiological role remains to be elucidated, sLOX-1 is emerging as a cardiovascular and metabolic risk factor, which highlights the need to identify interventions that reduce circulating levels of this receptor. In this regard, the main findings of the present study indicate that weight loss is a potential lifestyle therapy that warrants further investigation.