The Hepatic Glucocorticoid Receptor Is Crucial for Cortisol Homeostasis and Sepsis Survival in Humans and Male Mice

Abstract

Sepsis is hallmarked by hypercortisolemia, a stress response essential for survival. This elevation in plasma cortisol is partially brought about by suppressed hepatic cortisol breakdown. We demonstrate that a controlled downregulation of the hepatic glucocorticoid receptor (hepatic GR) is crucial. In a mouse model of fluid-resuscitated, antibiotic-treated abdominal sepsis and in human intensive care unit patients, sepsis reduced hepatic GR expression and signaling but increased (free) plasma cortisol/corticosterone, explained by suppressed cortisol/corticosterone-binding proteins and A-ring reductases. However, further experimental inhibition of hepatic GR with short hairpin RNA (shRNA) in septic mice increased mortality fivefold. Acutely, this further hepatic GR suppression prevented the rise in total corticosterone but further reduced binding proteins, resulting in elevated free corticosterone. After 3 days of shRNA-GR inhibition in sepsis, both total and free corticosterone levels were elevated, now explained by an additional reduction in A-ring reductase expression. Hepatic GR inhibition blunted the hyperglycemic stress response without causing hypoglycemia but also markedly increased circulating and hepatic inflammation markers and caused liver destruction, the severity of which explained increased mortality. In human sepsis, glucocorticoid treatment further suppressed hepatic GR expression, which could directly predispose to worse outcomes. In conclusion, sepsis partially suppressed hepatic GR expression, which appeared crucial to upregulate free cortisol/corticosterone availability. However, further sustained hepatic GR suppression evoked lethal excessive liver and systemic inflammation, independent of systemic cortisol/corticosterone availability.

Glucocorticoids in Sepsis: To Be or Not to Be

“…These results may imply that the inflammatory environment leads to reduced functioning of the GR. On the other hand, GC treatment further suppresses GR expression as was shown in human biopsy samples and this may predispose the patients to excessive inflammation, organ failure, and eventually death (34). Understanding the mechanisms underlying GCR opens avenues for reverting GCR in sepsis and applying GCs therapeutically.…”

“…PGC1a restoration or p300 overexpression restores GC responsiveness (72,96). GCR has been considered by some researchers as another good reason to treat sepsis patients with high stress doses of GCs (77), whereas other groups used GCR as an argument against the use of GCs in sepsis (34,97). On the one hand, GCR obviously limits the therapeutic use of GCs, since there is insufficient GR functioning.…”

ACTH and cortisol responses to CRH in acute, subacute, and prolonged critical illness: a randomized, double-blind, placebo-controlled, crossover cohort study

“…This should be done in validated animal models of prolonged critical illness [36]. A second limitation is that one cannot exclude additional suppression at the hypothalamic level from analgo-sedative drugs that are used throughout ICU stay, of which opioids are the main component [37].…”

“…A first limitation of this study is that, for obvious reasons, no hypothalamic and pituitary tissues were available for quantification of expression of CRH, vasopressin, ACTH, and of the CRH-receptor 1 and vasopressin-receptor. This should be done in validated animal models of prolonged critical illness [ 36 ]. A second limitation is that one cannot exclude additional suppression at the hypothalamic level from analgo-sedative drugs that are used throughout ICU stay, of which opioids are the main component [ 37 ].…”

Redefining the perioperative stress response: a narrative review

“…5 Translational murine studies also suggest that hepatic GR expression is reduced in sepsis, which reduces cortisol-binding proteins and suppresses α-ring reductases, resulting in increased free cortisol. 40…”