Pseudohypoadrenalism, a subclinical cortisol metabolism disorder in hyperuricemia

Abstract

Background: Hyperuricemia is a known risk factor of lipid metabolism disorder. However, the mechanisms have not been fully understood.

Methods: The serum samples from hyperuricemia subjects were used to analyze the correlation between serum uric acid and clinical characteristics. Hyperuricemia mice induced by potassium oxonate (PO) and adenine were used to explore glucocorticoid metabolism.

Results: In hyperuricemia patients, the levels of serum uric acid were positively correlated with the levels of γ-glutamyltransferase, associated with a cortisol metabolism disorder. In hyperuricemia state, the adrenal glands failed to respond to adrenocorticotropic hormone properly, leading to low cortisol, but not corticosterone production, and decreased mRNA levels of aldosterone synthase, 11β-hydroxylase, and 3β-hydroxysteroid dehydrogenase 1, three key enzymes for cortisol synthesis. The expression of both hepatic 5α-reductase and renal 11β-hydroxysteroid dehydrogenase 2 was significantly reduced, which led to low cortisol clearance. We denominated this cortisol metabolism disorder in hyperuricemia as pseudohypoadrenalism (PHAL).

Conclusion: PHAL increased exposure to the bioavailable cortisol in the liver, leading to local amplification of the biological action of corticosteroids. Unregulated biosynthesis pathway of bile acid expanded bile acid pool, and further aggravated cholestatic liver injury.

Keywords: cortisol; hyperuricemia; lipid metabolism disorder; liver injury; pseudohypoadrenalism.

Figure 1

Serum levels of C4, ALP and TBA were elevated in hyperuricemia mice (n=8). Normal control C57BL/6J mice group (Con), PO and adenine induced hyperuricemia mice group (HUA). (A) The body weight and food intake of control and hyperuricemia mice. (B) The organ index of control and hyperuricemia mice. (C) Serum uric acid level. (D) Serum cholesterol level. (E) Serum triglycerides level. (F) Serum BUN level. (G) Serum creatinine level. (H) Uric acid excretion in 24h urine. (I) Uric acid clearance in 24 h. (J) Creatinine clearance in 24 h. (K) Serum C4 level. (L) Serum ALP level. (M) Serum TBA level. (N) Serum GGT level. Data are presented as mean ± S.E.M. *p < 0.05, **p < 0.01, ***p < 0.001 vs control mice group.

Figure 2

Changes in the hepatic mRNA levels of genes involved in BA and cholesterol homeostasis in hyperuricemia mice. Normal control C57BL/6J mice group (Con), PO and adenine induced hyperuricemia mice group (HUA). (A) The mRNA levels of genes involved in bile acid synthesis. (B) The mRNA levels of genes involved in bile acid transport. (C) The mRNA levels of genes involved in cholesterol synthesis and transport. (D) The mRNA levels of genes involved in bile acid regulation. Data are presented as mean ± S.E.M. ^* p < 0.05, ^** p < 0.01, ^*** p < 0.001 vs control mice group.

Figure 3

Circulating cortisol levels decreased and 24 h urine free cortisol levels increased in hyperuricemia mice. Normal control C57BL/6J mice group (Con), PO and adenine induced hyperuricemia mice group (HUA). (A) The mRNA level of hepatic FGF21. (B) Serum cortisol level in hyperuricemia subjects. (C) Serum cortisol level in control and hyperuricemia mice. (D) Serum corticosterone level in control and hyperuricemia mice. (E) Serum CBG level in control and hyperuricemia mice. (F) 24 h urine free cortisol in control and hyperuricemia mice. (G) 24 h urine corticosterone in control and hyperuricemia mice. Data are presented as mean ± S.E.M. ^* p < 0.05, ^** p < 0.01, ^*** p < 0.001 vs control mice group.

Figure 4

Morphological analysis of the adrenal glands. Normal control C57BL/6J mice group (Con), PO and adenine induced hyperuricemia mice group (HUA). (A) Adrenal glands for H&E staining (20x). (B) The number of cells zona fasciculata of the adrenal gland. (C) Serum cortisol level of mice in ACTH stimulation test. (D, E) Serum ACTH and cortisol levels of mice in dexamethasone suppression test. Data are presented as mean ± S.E.M. ns, no significance ^* p < 0.05, ^** p < 0.01 vs control mice group.

Figure 5

The mRNA levels of genes involved in cortisol clearance and steroidogenesis decreased in hyperuricemia mice. Normal control C57BL/6J mice group (Con), PO and adenine induced hyperuricemia mice group (HUA). (A, B) The hepatic mRNA levels of 5α-reductase and 5β-reductase. (C, D) The mRNA levels of genes involved in regenerating cortisol from inactive cortisone. (E, F) The hepatic mRNA levels of glucocorticoid receptor α and β. (G–L) The mRNA levels of steroidogenesis‐related genes in mouse adrenals. Data are presented as mean ± S.E.M. ^* p < 0.05, ^** p < 0.01, ^*** p < 0.001 vs control mice group.