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Int. J. Mol. Sci. 2017, 18(11), 2389; https://doi.org/10.3390/ijms18112389

Glucocorticoids Cause Gender-Dependent Reversal of Hepatic Fibrosis in the MDR2-Knockout Mouse Model

1
Department of Medical Physiology, Texas A & M Health Science Center College of Medicine, Temple, TX 76504, USA
2
Central Texas Veterans Health Care System, Temple, TX 76504, USA
*
Author to whom correspondence should be addressed.
Received: 31 October 2017 / Revised: 6 November 2017 / Accepted: 6 November 2017 / Published: 10 November 2017
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Abstract

Hepatic cholestasis is associated with a significant suppression of the hypothalamus-pituitary-adrenal axis (HPA). In the present study, we tested the hypothesis that activation of the HPA axis by corticosterone treatment can reverse liver inflammation and fibrosis in a multidrug resistance protein 2 knockout (MDR2KO) transgenic mouse model of hepatic cholestasis. Friend Virus B NIH-Jackson (FVBN) control and MDR2KO male and female mice were treated with vehicle or corticosterone for two weeks, then serum and liver analyses of hepatic cholestasis markers were performed. Indicators of inflammation, such as increased numbers of macrophages, were determined. MDR2KO mice had lower corticotropin releasing hormone and corticosterone levels than FVBN controls in the serum. There was a large accumulation of CD68 and F4/80 macrophages in MDR2KO mice livers, which indicated greater inflammation compared to FVBNs, an effect reversed by corticosterone treatment. Intrahepatic biliary duct mass, collagen deposition and alpha smooth muscle actin (αSMA) were found to be much higher in livers of MDR2KO mice than in controls; corticosterone treatment significantly decreased these fibrosis markers. When looking at the gender-specific response to corticosterone treatment, male MDR2KO mice tended to have a more pronounced reversal of liver fibrosis than females treated with corticosterone. View Full-Text
Keywords: hypothalamic-pituitary-adrenal (HPA) axis; corticosterone; glucocorticoid receptor; hepatic cholestasis; liver fibrosis; cholangiocytes hypothalamic-pituitary-adrenal (HPA) axis; corticosterone; glucocorticoid receptor; hepatic cholestasis; liver fibrosis; cholangiocytes
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited (CC BY 4.0).
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Petrescu, A.D.; Grant, S.; Frampton, G.; Kain, J.; Hadidi, K.; Williams, E.; McMillin, M.; DeMorrow, S. Glucocorticoids Cause Gender-Dependent Reversal of Hepatic Fibrosis in the MDR2-Knockout Mouse Model. Int. J. Mol. Sci. 2017, 18, 2389.

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