Estrogen Deficiency Promotes Hepatic Steatosis via a Glucocorticoid Receptor-Dependent Mechanism in Mice

Abstract

SUMMARY Glucocorticoids (GCs) are master regulators of systemic metabolism. Intriguingly, Cushing’s syndrome, a disorder of excessive GCs, phenocopies several menopause-induced metabolic pathologies. Here, we show that the glucocorticoid receptor (GR) drives steatosis in hypogonadal female mice because hepatocyte-specific GR knockout mice are refractory to developing ovariectomy-induced steatosis. Intriguingly, transcriptional profiling revealed that ovariectomy elicits hepatic GC hypersensitivity globally. Hypogonadism-induced GC hypersensitivity results from a loss of systemic but not hepatic estrogen (E2) signaling, given that hepatocyte-specific E2 receptor deletion does not confer GC hypersensitivity. Mechanistically, enhanced chromatin recruitment and ligand-dependent hyperphosphorylation of GR underlie ovariectomy-induced glucocorticoid hypersensitivity. The dysregulated glucocorticoid-mediated signaling present in hypogonadal females is a product of increased follicle-stimulating hormone (FSH) production because FSH treatment in ovary-intact mice recapitulates glucocorticoid hypersensitivity similar to hypogonadal female mice. Our findings uncover a regulatory axis between estradiol, FSH, and hepatic glucocorticoid receptor signaling that, when disrupted, as in menopause, promotes hepatic steatosis.

Predictors of advanced fibrosis in elderly patients with biopsy-confirmed nonalcoholic fatty liver disease: The GOASIA study

“…The gender difference of the metabolic disturbance is most evident in postmenopausal women. Although the mechanism of menopause-induced metabolic dysfunction are largely unknown, estrogen depletion is thought to responsible for the underlying pathological mechanism (31). This observation requires further study to confirm.…”

Predictors of advanced fibrosis in elderly patients with biopsy-confirmed nonalcoholic fatty liver disease: the GOASIA study

“…The gender difference of the metabolic disturbance is most evident in postmenopausal women. Although the mechanisms of menopause-induced metabolic dysfunction are largely unknown, estrogen depletion is thought to responsible for the underlying pathological mechanism [31]. This observation requires further study to confirm.…”

The glucocorticoid receptor agonistic modulators CpdX and CpdX-D3 do not generate the debilitating effects of synthetic glucocorticoids

“…Bilateral ovariectomy in mice was performed as described in ref. 35. Breeding, maintenance, and experimental manipulation of mice were approved by the animal care and use committee of the IGBMC/ICS.…”

“…In Marked Contrast with Dex, a 1-Mo Treatment with CpdX Decreases the Plasmatic Glucose Level and Liver Lipid Deposition in OVX Mice. It has been reported that an estrogen deficiency can lead to hyperglycemia and a fatty liver lipid deposition in the liver of postmenopausal women (34) as well as in the livers of 4-mo-old mice that were OVX at the age of 4 wk (35). It is also known that a long-term treatment with GCs (Dex) can aggravate these metabolic and hepatic syndromes (35).…”

“…It has been reported that an estrogen deficiency can lead to hyperglycemia and a fatty liver lipid deposition in the liver of postmenopausal women (34) as well as in the livers of 4-mo-old mice that were OVX at the age of 4 wk (35). It is also known that a long-term treatment with GCs (Dex) can aggravate these metabolic and hepatic syndromes (35). To investigate whether a CpdX administration could possibly prevent the occurrence of such syndromes in postmenopausal women, bilaterally OVX mice were taken as surgical models for menopause.…”