In this study we evaluated the adverse effects of HDL-C in concentrations of less than 1.3 mmol/L in women with high risk for CVD, mainly a population classified with MetS and the additional risk factor of plasma LDL-C ≥ 2.6 mmol/L. Our data analysis suggests that HDL-C < 1.3 mmol/L further increases the risk of CVD and atherosclerosis. The novel aspect of this study is that L-HDL appears to be a biomarker of elevated concentrations of circulating atherogenic lipoproteins as well as increased insulin resistance and lower concentrations of adiponectin, all of which are key biomarkers of increased risk for type 2 diabetes and coronary heart disease. Although participants in this study had dietary habits that might increase risk for heart disease such as a high intake of trans fatty acids and low intakes of omega-3 fatty acids and dietary fiber, high simple sugar intake and high glycemic load were the dietary components that might have been correlated with low concentrations of HDL-C.
A main concern regarding MetS is the predisposition to glucose intolerance, insulin resistance, and diabetes [2
]. The consumption of foods with a low glycemic index has been advocated for amelioration of dysfunctional glucose metabolism for more than two decades [20
]. Diets based on varying degrees of carbohydrate restriction also have demonstrated efficacy in improving glucose metabolism and associated metabolic aberrations [10
]. In the present, study, the women with lower HDL-C (< 1.3 mmol/L) consumed more sugar and had higher glycemic loads than those from the H-HDL group. Interestingly, women from the L-HDL groups also consumed less alcohol and less saturated fat. Moderate increases in alcohol have been correlated with higher HDL-C and paraoxanase-1, suggesting a protective effect against CVD [21
], and all fatty acids including saturated fatty acids (with the exception of trans fat) have been correlated with increased HDL-C [22
]. Thus, the above results are not surprising.
The women with L-HDL also had higher concentrations of plasma insulin and greater insulin resistance as determined by HOMA, along with lower concentrations of adiponectin. In agreement with our results, low adiponectin concentrations are strongly correlated with insulin resistance [23
]. Data from epidemiological studies also indicate that circulating adiponectin is reduced in patients with CVD and diabetes [24
]. To further support our findings that HDL-C concentrations predict insulin resistance, in a recent study, TG/HDL-C was used as a marker of insulin resistance in obese patients [25
]. In the present study, plasma TG levels did not differ between groups and subjects from the H-HDL group had higher apo C-III than those from the L-HDL group. These findings suggest that the higher levels of apo C-III in the H-HDL group were related to the increased number of HDL particles available to transport this apolipoprotein. While apo C-III present in VLDL is associated with decreased lipoprotein lipase activity, apo C-III transported by HDL indicates a reservoir of this apolipoprotein [26
]. Overall, subjects from the L-HDL group appear to be at greater risk for the development of diabetes as documented by more elevated insulin resistance and lower levels of adiponectin.
Subjects with L-HDL presented increased concentrations of the atherogenic lipoproteins large VLDL, small LDL, and IDL. Furthermore, these women had lower concentrations of the larger, more buoyant LDL that is considered less atherogenic [27
]. In addition, impaired endothelial function can be assessed by measuring the level of molecules secreted by the endothelium, such as sICAM1 [28
]. Subjects with L-HDL had increased concentrations of this adhesive molecule, which poses at higher risk for CVD.
Abnormalities in VLDL particle size seem to be a major contributing factor to dysfunctional lipoprotein metabolism [29
]. Large VLDL particles are classified as atherogenic for two main reasons: their ability to interact with macrophages in the arterial wall [30
] and their easy conversion to small LDL [31
]. In addition to transporting high concentrations of plasma TG, large VLDL also carry high concentrations of cholesterol (5 times more than an LDL particle) [30
]. These large VLDL are taken up by macrophages through cell surface membrane-binding proteins leading to the formation of foam cells and the initiation of atherosclerosis. In addition, through the delipidation cascade, TG-rich VLDL are precursors for the formation of small, dense LDL particles and increased HDL catabolism [32
]. The phenotype characterized by a predominance of small LDL particles has been termed pattern B
and is typical of MetS and diabetes [27
]. Small, dense LDL particles are considered more atherogenic due to their decreased binding to the LDL receptor, leading to increased plasma residence time and an increased susceptibility to oxidation [33
]. In addition, increased levels of small LDL in plasma are associated with increased risk of coronary heart disease [33
]. IDL, also known as VLDL remnants, are part of TG-rich lipoproteins and are associated with increased risk for heart disease [34
]. All of these atherogenic lipoproteins were higher in women with lower concentrations of HDL-C. Another observation was that the groups of women with HDL-C > 1.3 mmol/L had lower numbers of both total HDL and large HDL particles. Since the main function of HDL is to remove cholesterol and oxysterols from extra-hepatic cells including smooth muscle cells, endothelial cells, and macrophages through ABCA1 and ABCG1 transporters [35
], a higher number of particles suggest a more efficient reverse cholesterol transport and increased protection against atherosclerosis.
Both Lp(a) levels and oxidized LDL concentrations did not differ between HDL groups. Plasma Lp(a) concentrations are reported to have a strong ethnic influence and is correlated with increased risk for heart disease both through its atherogenic and prothrombotic properties [36
]. Specifically, concentrations > 0.71-1.07 µmol/L are associated with 1.5- to 3-fold increases of coronary atherosclerosis independent of plasma levels of other lipoproteins [36
]. In the current study with women at high risk for CVD, levels of Lp(a) varied between 0.21 and 4.14 µmol/L. Low HDL-C was not associated with higher concentrations of Lp(a) in this group of women. Oxidized LDL has been correlated with atherosclerosis, diabetes, and renal disease [37
]. Small significant amounts of oxidized LDL have been detected in plasma by use of monoclonal antibodies specific to epitopes of oxidized apo B [17
]. Among these, 4E6 recognizes MDA modified lysine epitopes and has been extensively used in human studies [17
]. Similar to our findings for Lp(a), the women in the current study presented a wide range of oxidized LDL, from 1.4 to 445 µgl/L. In this group of women, concentrations of both biomarkers, Lp(a) and oxidized LDL, for increased risk of CVD, were independent of HDL-C concentrations.
The data from this study suggest that low plasma HDL-C (< 1.3 mmol/L) is associated with increased risk of CVD and diabetes in women already at risk, and appears to be a biomarker of a greater atherogenic lipoprotein profile (decreased large VLDL and small LDL). In addition, low concentrations of HDL-C are related to a lower number of HDL particles, decreased HDL size, and decreased large HDL, conditions that suggest the existence of a less efficient reverse cholesterol transport. Finally, individuals with low concentrations of HDL-C were at increased risk for diabetes, as they presented increased insulin resistance and lower concentrations of adiponectin.