Pathophysiology of dyslipidemia in Cushing's 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, very-low-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 fat where lipolysis is activated, resulting in the release of free fatty acids into the circulation. The increase of free fatty acids may enhance the accumulation of hepatic lipids reducing glucose uptake and activating various serine kinases which results in decreased insulin signaling. Moreover, mice with a liver-specific disruption of the glucocorticoid receptor had diminished hepatic triglycerides levels. In humans, a high prevalence (up to 20%) of hepatic steatosis was also reported in patients with Cushing's syndrome. Genetic variations in the glucocorticoid receptors may also affect the activity of cortisol, lipid metabolism and cardiovascular risk.
Arnaldi
Giorgio
G
Division of Endocrinology, Department of Internal Medicine, Polytechnic University of Marche Region, Ancona, Italy. arnaldi.giorgio@libero.it
Scandali
Valerio Mattia
VM
Trementino
Laura
L
Cardinaletti
Marina
M
Appolloni
Gloria
G
Boscaro
Marco
M
D000818:Animals; D003480:Cushing Syndrome / Q000150:complications* / Q000378:metabolism; D050171:Dyslipidemias / Q000209:etiology* / Q000378:metabolism; D005227:Fatty Acids / Q000378:metabolism*; D005938:Glucocorticoids / Q000378:metabolism; D006801:Humans; D007328:Insulin / Q000378:metabolism; D008099:Liver / Q000378:metabolism*
D005227:Fatty Acids; D005938:Glucocorticoids; D007328:Insulin