Pathophysiology of Dyslipidemia in Cushings Syndrome

Dyslipidemia seems to be less frequent than other metabolic comorbidities in human Cushing’s syndrome. Nevertheless, it plays an important role in determining the global cardiovascular risk in overt and subclinical Cushing’s syndrome. In Cushing’s syndrome, there is an increase of triglyceride and total cholesterol levels whereas HDL can be at variable levels. Overt and subclinical Cushing’s syndrome share many features with metabolic syndrome including insulin resistance, abnormal fasting glucose levels, hypertension, obesity and dyslipidemia. The pathogenetic mechanisms are multifactorial, including direct and indirect cortisol action on lipolysis, free fatty acid production and turnover, verylow-density lipoprotein synthesis and fatty accumulation in the liver. AMP-activated protein kinase mediates many of glucocorticoid-induced metabolic changes. Insulin resistance plays a key role in determining lipid abnormalities. Other hormonal changes are involved including growth hormone, testosterone in men and estrogen in women, catecholamines and cytokines. In vitro, cortisol increases lipoprotein lipase in adipose tissues and particularly in visceral Published online: September 10, 2010 Giorgio Arnaldi Clinica di Endocrinologia, Azienda Ospedaliero-Universitaria Ospedali Riuniti di Ancona IT–60100 Ancona (Italy) Tel. +39 071 887 061, Fax +39 071 887 300, E-Mail arnaldi.giorgio @ libero.it © 2010 S. Karger AG, Basel 0028–3835/10/0925–0086$26.00/0 Accessible online at: www.karger.com/nen D ow nl oa de d by : 54 .7 0. 40 .1 1 11 /2 2/ 20 17 7 :1 2: 56 P M Pathophysiology of Dyslipidemia in Cushing’s Syndrome Neuroendocrinology 2010;92(suppl 1):86–90 87 tients with exogenous and endogenous glucocorticoid excess [1, 2] . Several studies have suggested that long-term glucocorticoid therapy can cause dyslipidemia. However, a recent survey on 15,004 patients demonstrated that glucocorticoid use was not associated with an adverse lipid profile but with higher high-density lipoprotein (HDL) cholesterol among patients aged 60 years or older [1] . On the contrary, a clear glucocorticoid dose-response relation with BMI, triglyceride, total cholesterol, and lowdensity lipoprotein (LDL) levels was found in 1,707 hypopituitary patients on glucocorticoid replacement treatment [3] . Dyslipidemia is one of the features of human Cushing’s syndrome including – in association with central obesity – hypertension, impaired glucose tolerance or diabetes, insulin resistance, hypercoagulability, and it determines an increased cardiovascular risk. In Cushing’s syndrome, there is an increase in circulating very-lowdensity lipoprotein (VLDL) and LDL, but not high-density lipoprotein (HDL), with consequent elevation of triglycerides and total cholesterol levels [2] . These alterations normalize or improve after correction of hypercortisolism. In our series of 49 patients with Cushing’s syndrome, total and LDL cholesterol were correlated with morning plasma cortisol and with cortisolemia after lowdose dexamethasone (Dex) suppression test. Interestingly, in contrast to other studies and in patients with metabolic syndrome (this condition shares many features with Cushing’s syndrome), HDL-cholesterol levels were not reduced [4] . Subclinical hypercortisolism is also often associated with insulin resistance, abnormal fasting glucose levels, hypertension, obesity and dyslipidemia (high triglycerides and low HDL levels) [2] . This paper provides an update of the current knowledge on the pathophysiology of glucocorticoid-induced dyslipidemia where cellular and molecular mechanisms involved are multifactorial including direct and indirect cortisol-induced activity. Lipolytic Actions of Glucocorticoids Glucocorticoids regulate differentiation, function and distribution of adipose tissue. Glucocorticoids’ effects on lipid metabolism in adipose tissue are controversial and may involve stimulation of both lipolysis and lipogenesis [5, 6] . They can promote pre-adipocyte differentiation and inhibit adipose stromal cell proliferation, triggering a cascade of differentiation-dependent genes to facilitate adipogenesis. Glucocorticoids increase lipolysis in peripheral fat depots while promoting pre-adipocyte differentiation in central fat. Moreover, glucocorticoids may act synergistically with insulin to upregulate lipogenesis [5] . Recently, it has been demonstrated that glucocorticoids directly stimulate lipolysis in rat primary adipocytes in a doseand time-dependent manner [7] . In this study, Dex stimulated the release of free fatty acids (FFA) and glycerol after 24 h of incubation. This action occurred even at a low Dex concentration; it was rapid starting at 4–8 h and increased continually to 32 h. The findings that Dex increased intracellular cAMP levels and protein kinase A (PKA) activity and down-regulated cyclic-nucleotide phosphodiesterase 3B, the major enzyme responsible for cAMP hydrolysis, suggest that cAMP/ PKA system is functionally involved in the mechanism by which glucocorticoids stimulate lipolysis. Furthermore, incubation with Dex caused phosphorylation and downregulation of perilipin, a phosphoprotein that coats lipid droplets in adipocytes which regulates lipolysis. Phosphorylated perilipin changes conformation and, exposing the stored lipids, facilitates lipolysis [7] . Confirming previous studies, Xu et al. [7] showed that Dex significantly upregulated expression and promoted activity of hormone-sensitive lipase (HSL) and adipose triglycerides lipase, the two major lipases in adipocytes. However, Dex did not induce HSL translocation to the lipid droplets in differentiated adipocytes showing that Dex stimulation is weaker or different from typical PKA activation due to catecholamine. That same study by Xu and coworkers [7] evaluated the in vivo lipolysis in epididymal adipose tissues isolated from male rats treated with Dex. In treated rats, Dex greatly increased FFA plasma concentration at 6 weeks and this was associated with increased lipase activity and lipolysis in adipose tissues. In human adipocytes, Dex increased LPL mRNA and activity, and these effects were more marked in the omental adipose tissue, particularly in men. The maximum activity of LPL induced by insulin or insulin plus Dex was higher in the subcutaneous depot of women. In conclusion, there were differences between sexes and adipose depots studied [5] . Glucocorticoids may enhance lipolysis and modulate FFA mobilization through multiple mechanisms including a permissive effect, which has long been thought to be the principal one. In particular, glucocorticoids may modulate the dynamic responsiveness to other hormones D ow nl oa de d by : 54 .7 0. 40 .1 1 11 /2 2/ 20 17 7 :1 2: 56 P M Arnaldi/Scandali/Trementino/ Cardinaletti/Appolloni/Boscaro Neuroendocrinology 2010;92(suppl 1):86–90 88 such as catecholamines and GH, thereby increasing their lipolytic action [6] . In vitro studies showed a combined lipolytic effect of GH and cortisol exceeding the GH-induced lipolysis in human subcutaneous abdominal adipose tissue. A recent study examined the effect of GH, in both the absence and presence of Dex on lipolysis by omental adipose tissue explants from obese women in primary culture. An enhancement of lipolysis by GH in the presence of Dex but not by Dex or GH alone was observed. There was also a significant further stimulation by GH in the presence of Dex of hormone-sensitive lipase, perilipin, lipoprotein lipase and beta1 adrenergic receptor mRNA [8] . In a single-blinded, placebo-controlled, randomized in vivo study, GH and cortisol stimulate systemic and regional lipolysis independently and in an additive manner when coadministered in healthy men. Glucocorticoids Effects on Hepatic Fatty Acid