Adrenal cortex renewal in health and disease

Lyraki, Rodanthi; Schedl, Andreas

doi:10.1038/s41574-021-00491-4

Cited by 46 publications

(35 citation statements)

References 183 publications

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“…On the other hand, an increased prevalence of adrenal diseases has been reported in patients without signs and symptoms specific of adrenal disorders but affected by chronic diseases or conditions (ie diabetes, hypertension, osteoporosis, depression, fibromyalgia, hypotension) that are often misdiagnosed as 'idiopathic' but which should instead be attributed to observed alterations in adrenal function (1)(2)(3)(4)(5)(6)(7). Such an expansion in knowledge of the role of adrenal hormones in the pathophysiology of common human diseases is in accordance with well-known evidence arising from studies in mammals that adrenal hormones influence several functions, including different metabolic pathways, immune responses, cognition, circadian rhythms, saline homeostasis, blood pressure control and stress response (8). However, more recently, not only has the degree of secretion of adrenal hormones been suggested, but also their metabolism and sensitivity within peripheral target tissues have been suggested to play a role in the development of chronic disorders such as hypertension, diabetes, osteoporosis, and mood disorders, even in subjects with biochemically normal adrenal function (9)(10)(11)(12)(13)(14)(15)(16)(17)(18).…”

Section: Introductionsupporting

confidence: 53%

Grand Challenge in Adrenal Endocrinology: Is the Legacy of the Past a Challenge for the Future of Precision Medicine?

Chiodini

Gennari

2021

Front. Endocrinol.

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Section: Introductionsupporting

confidence: 53%

Grand Challenge in Adrenal Endocrinology: Is the Legacy of the Past a Challenge for the Future of Precision Medicine?

Chiodini

Gennari

2021

Front. Endocrinol.

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“…As for bilateral adrenal tumors, somatic alteration of actors of the cAMP/PKA pathway were found in unilateral cortisol-secreting adenomas. Mutations of the catalytic alpha subunit of the PKA enzyme (PRKACA) are often present in patients with unilateral adenomas and are related to clinically overt Cushing’s syndrome [ 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 ], while they have been rarely (less than 5% of cases) detected in patients with mHC [ 10 ]. At variance, whole exome sequencing investigations revealed a high prevalence of mutations of CTNNB1, the gene encoding β-catenin, in patients with mHC.…”

Section: Pathophysiology Of Pituitary and Adrenal Mild Hypercortisolismmentioning

confidence: 99%

Pathophysiology of Mild Hypercortisolism: From the Bench to the Bedside

Favero

Cremaschi

Parazzoli

et al. 2022

IJMS

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Mild hypercortisolism is defined as biochemical evidence of abnormal cortisol secretion without the classical detectable manifestations of overt Cushing’s syndrome and, above all, lacking catabolic characteristics such as central muscle weakness, adipose tissue redistribution, skin fragility and unusual infections. Mild hypercortisolism is frequently discovered in patients with adrenal incidentalomas, with a prevalence ranging between 5 and 50%. This high variability is mainly due to the different criteria used for defining this condition. This subtle cortisol excess has also been described in patients with incidentally discovered pituitary tumors with an estimated prevalence of 5%. To date, the mechanisms responsible for the pathogenesis of mild hypercortisolism of pituitary origin are still not well clarified. At variance, recent advances have been made in understanding the genetic background of bilateral and unilateral adrenal adenomas causing mild hypercortisolism. Some recent data suggest that the clinical effects of glucocorticoid (GC) exposure on peripheral tissues are determined not only by the amount of the adrenal GC production but also by the peripheral GC metabolism and by the GC sensitivity. Indeed, in subjects with normal cortisol secretion, the combined estimate of cortisol secretion, cortisone-to-cortisol peripheral activation by the 11 beta-hydroxysteroid dehydrogenase enzyme and GC receptor sensitizing variants have been suggested to be associated with the presence of hypertension, diabetes and bone fragility, which are three well-known consequences of hypercortisolism. This review focuses on the pathophysiologic mechanism underlying both the different sources of mild hypercortisolism and their clinical consequences (bone fragility, arterial hypertension, subclinical atherosclerosis, cardiovascular remodeling, dyslipidemia, glucose metabolism impairment, visceral adiposity, infections, muscle damage, mood disorders and coagulation).

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“…Under a normal physiological condition, ∼80% of cholesterol used in adrenal cortex hormone synthesis is derived from circulating lipoproteins, such as scavenger receptor class B, type I (SR-BI)-mediated selective uptake of cholesteryl ester from high-density lipoprotein (HDL) and low-density lipoprotein receptor (LDLR)-mediated endocytosis of LDL (1). The remaining cholesterol is contributed by de novo biosynthesis from acetate via the mevalonate pathway (2,3), in which 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR) is the rate-limiting enzyme (4,5). Cholesterol is stored as cholesteryl ester (CE) in lipid droplets in the adrenal cortex (2,6,7), which can be converted to free cholesterol by lipase-mediated lipolysis as needed for steroidogenesis (8)(9)(10).…”

Section: Introductionmentioning

confidence: 99%

“…Adrenal insufficiency characterized by low blood levels of cortisol and aldosterone can lead to a series of systemic clinical symptoms, including hypotension, anorexia, fatigue, syncope, hyponatremia, sexual dysfunction, mental disorders, etc. (3). Surfeit 4 (Surf4) is a cargo receptor resided on the endoplasmic reticulum (ER) membrane, where it facilitates the transport of secretory proteins from the ER to the Golgi apparatus.…”

Section: Introductionmentioning

confidence: 99%

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Loss of Hepatic Surf4 Depletes Lipid Droplets in the Adrenal Cortex but Does Not Impair Adrenal Hormone Production

Chang

Zhao

Qin

et al. 2021

Front. Cardiovasc. Med.

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The adrenal gland produces steroid hormones to play essential roles in regulating various physiological processes. Our previous studies showed that knockout of hepatic Surf4 (Surf4LKO) markedly reduced fasting plasma total cholesterol levels in adult mice, including low-density lipoprotein and high-density lipoprotein cholesterol. Here, we found that plasma cholesterol levels were also dramatically reduced in 4-week-old young mice and non-fasted adult mice. Circulating lipoprotein cholesterol is an important source of the substrate for the production of adrenal steroid hormones. Therefore, we investigated whether adrenal steroid hormone production was affected in Surf4LKO mice. We observed that lacking hepatic Surf4 essentially eliminated lipid droplets and significantly reduced cholesterol levels in the adrenal gland; however, plasma levels of aldosterone and corticosterone were comparable in Surf4LKO and the control mice under basal and stress conditions. Further analysis revealed that mRNA levels of genes encoding enzymes important for hormone synthesis were not altered, whereas the expression of scavenger receptor class B type I (SR-BI), low-density lipoprotein receptor (LDLR) and 3-hydroxy-3-methyl-glutaryl-CoA reductase was significantly increased in the adrenal gland of Surf4LKO mice, indicating increased de novo cholesterol biosynthesis and enhanced LDLR and SR-BI-mediated lipoprotein cholesterol uptake. We also observed that the nuclear form of SREBP2 was increased in the adrenal gland of Surf4LKO mice. Taken together, these findings indicate that the very low levels of circulating lipoprotein cholesterol in Surf4LKO mice cause a significant reduction in adrenal cholesterol levels but do not significantly affect adrenal steroid hormone production. Reduced adrenal cholesterol levels activate SREBP2 and thus increase the expression of genes involved in cholesterol biosynthesis, which increases de novo cholesterol synthesis to compensate for the loss of circulating lipoprotein-derived cholesterol in the adrenal gland of Surf4LKO mice.

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Adrenal cortex renewal in health and disease

Cited by 46 publications

References 183 publications

Grand Challenge in Adrenal Endocrinology: Is the Legacy of the Past a Challenge for the Future of Precision Medicine?

Grand Challenge in Adrenal Endocrinology: Is the Legacy of the Past a Challenge for the Future of Precision Medicine?

Pathophysiology of Mild Hypercortisolism: From the Bench to the Bedside

Loss of Hepatic Surf4 Depletes Lipid Droplets in the Adrenal Cortex but Does Not Impair Adrenal Hormone Production

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