In this study, we provide the first comprehensive report of lipoprotein profile, including particle size and sub-species concentrations, among obese patients in whom GH secretory capacity was characterized. Our data demonstrate a significant association between peak stimulated GH on standard stimulation testing and LDL and HDL particle size. The results suggest that reduced peak stimulated GH is associated with a more atherogenic lipoprotein profile with decreased LDL and HDL particle size, which may contribute to the increased CVD risk associated with reduced GH secretion in obesity. In our data, peak stimulated GH was not associated with oxidized LDL.
For the purposes of this study, we used the median peak stimulated GH value among obese subjects to define relative GH sufficiency or deficiency of obesity. Using this cut-off value of 6.25 μg/l, we obtained equal numbers of obese subjects with relative GH sufficiency or deficiency and demonstrated a strong relationship of GH status on LDL and HDL particle size. More importantly, we demonstrate a continuum of abnormality in lipoprotein particle size and subspecies concentrations associated with reduced GH secretory capacity as demonstrated in the univariate analyses and confirmed in the multivariate analyses.
Previous studies have demonstrated an association between small dense LDL cholesterol particles and increased CVD 3
and small HDL particles have also been associated with the presence of coronary artery disease 14
. Our results demonstrate a significant association between reduced GH secretion in obesity and reduced LDL and HDL particle size with a shift to a greater concentration of smaller LDL and HDL particles. The shift in the specific lipoprotein sub-species and size may contribute to the recently demonstrated association between reduced GH secretion and increased CVD risk in obesity 1, 2
As age, gender, race, ethnicity and insulin resistance have been shown to play a role in lipoprotein distribution 8-13
, we controlled for these covariates, as well as the use of lipid lowering medications and their respective serum cholesterol levels, in our multivariate regression modeling. Our results suggest the association of peak stimulated GH with LDL and HDL particle size may be independent from the effects of these covariates.
The current study was not designed to specifically address the mechanism through which reduced GH secretion in obesity may be associated with circulating lipoprotein concentrations or particle size. Previous studies have demonstrated GH reduces total cholesterol in hypercholesterolemic and normocholesterolemic men 15
either through induction of hepatic LDL receptor to potentiate clearing of LDL 16
or through activation of cholesterol 7α-hydroxylase to metabolize cholesterol to bile acids 17
or even through decreased de novo lipogenesis as seen in subjects with HIV infection 18
. In regards to particle size, LDL particle size is inversely related to hepatic lipase activity 19
. As hepatic lipase activity is low in conditions of GH excess such as acromegaly 20, 21
, reduced GH secretion associated with obesity may be associated with elevated hepatic lipase activity contributing to reduced LDL particle size. The size of the lipoprotein particles, HDL and VLDL/chylomicrons in particular, may also be affected by the activity of cholesterol ester transfer protein (CETP) which is expressed in the GH target organs of adipose tissue and liver 22
. While GH excess, as seen in acromegaly, was associated with higher plasma CETP activity in one study 20
, another study demonstrated reduced CETP activity in acromegaly and an inverse association between plasma IGF-1 levels and CETP activity 23
. GH treatment has also been shown to decrease CETP 24, 25
, further supporting this negative association. Increased CETP activity in the setting of reduced GH secretion in obesity may result in increased transfer of cholesterol esters from HDL to VLDL/chylomicrons and IDL resulting in smaller, more dense HDL particles and to larger VLDL/chylomicrons and IDL particles, as seen in our study. The combination of increased CETP activity and hepatic lipase activity also may contribute to the formation of more dense, lipid poor, LDL particles.
Interestingly, while peak stimulated GH remained significantly associated with both LDL and HDL particle size independent of measures of insulin resistance, VLDL particle size was related to HOMA IR and not peak GH in multivariate modeling. This suggests that for VLDL particle size, unlike for LDL and HDL, insulin resistance rather than peak GH is a primary determinant of particle size. This is consistent with the known role of insulin in VLDL metabolism and the association between insulin resistance and hypertriglyceridemia 26
. Previous studies have demonstrated the increase in VLDL particle size associated with insulin resistance occurs primarily due to an increases in the concentration of circulating large VLDL particles without significant changes in the concentrations of small or medium VLDL particles 27
. This pattern of VLDL particle concentration is confirmed in our subset of obese subjects with reduced GH secretion and may reflect the increased insulin resistance seen in this sub-group of obese subjects.
One potential explanation for our data is that obesity results in reduced GH, and reduced GH further contributes to abnormal lipoprotein particle size in obesity. However, this study is limited by its observational nature and we can not conclude whether the changes in lipoprotein sub-species are a consequence of the reduced GH secretion. Therefore an alternative explanation for our data could involve other covariates such as age, BMI and insulin resistance which may affect lipoprotein particle size independent of GH. Although we controlled for these factors statistically using multivariate modeling, further interventional studies would be necessary to demonstrate whether normalization of the reduced GH secretion would yield any beneficial effects on specific lipoprotein profiles in obesity. Nonetheless, this study is the first study to perform a detailed evaluation of the association between GH secretion and various lipoprotein particle size and sub-species using proton NMR spectroscopy and suggests a potential relationship between reduced GH and a more atherogenic lipoprotein particle size in obesity. In addition, we characterized GH secretory capacity using a standardized GHRH-arginine test. We did not characterize endogenous GH secretion including various pulsatility parameters which would have been difficult in a study of this size but may relate differentially to lipoprotein particle size. Lastly, the obese GHD subjects, compared to the obese GHS subjects, were older, with more central obesity and tended to be male. This is consistent with the known effects of these covariates, particularly, central obesity, on GH secretion, and may account for some of the more unfavorable lipoprotein characteristics. However, we control for these covariates and report both an un-adjusted and an adjusted P value in the stratified analyses. Furthermore, the relationship between GH and lipoprotein particle size and sub-species concentrations was also demonstrated on univariate analyses including all subjects and in more complex multivariate modeling. Further studies are needed into the mechanism by which reduced GH secretion may contribute to abnormal lipoprotein particle size in obesity.
In summary, we demonstrate a more adverse LDL and HDL subpopulation distribution in obese subjects with reduced GH secretion. These changes were independent of obesity and insulin resistance and may contribute to the increased CVD risk previously demonstrated in obese subjects with reduced GH secretion. Further interventional studies are now needed to demonstrate whether improvement of reduced GH secretion by exogenous GH or GH releasing factors would provide beneficial effects on lipoprotein profile and cardio-metabolic risk associated with obesity.