title: Endogenous glucocorticoids exacerbate cholestasis-associated liver injury and hypercholesterolemia in mice.
abstract: Cholestatic liver disease is characterized by a disruption of bile flow, bile acid toxicity, liver injury, and hypercholesterolemia. Relatively high secretion of glucocorticoids by the adrenals has been observed under cholestatic conditions. Here we investigated a contribution of the rise in endogenous glucocorticoids to initial stage cholestasis pathology. Adrenalectomized or sham-operated control C57BL/6 mice were given an oral dose of alpha-naphthylisothiocyanate to induce cholestasis. Adrenalectomy effectively lowered plasma corticosterone levels (18±5ng/ml vs 472±58ng/ml; P<0.001) and disrupted the metabolic and anti-inflammatory glucocorticoid function. Adrenal removal did not exacerbate the cholestasis extent. In contrast, the cholestasis-associated liver injury was markedly lower in adrenalectomized mice as compared to controls as evidenced by a 84%-93% decrease in liver necrosis and plasma alanine aminotransferase and bile acid levels (P<0.001 for all). Gene expression analysis on livers from adrenalectomized mice suggested the absence of bile acid toxicity-associated farnesoid X receptor signaling in the context of a 44% (P<0.01) and 82% (P<0.001) reduction in sodium/bile acid cotransporter member 1 transcript level as compared to respectively control and non-diseased mice. Adrenalectomy reduced the expression of the cholesterol synthesis gene HMG-CoA reductase by 70% (P<0.05), which translated into a 73% lower plasma total cholesterol level (P<0.05). Treatment of C57BL/6 mice with the glucocorticoid receptor antagonist RU-486 recapitulated the protective effect of adrenalectomy on indices of liver injury and hypercholesterolemia. In conclusion, we have shown that endogenous glucocorticoids exacerbate the liver injury and hypercholesterolemia associated with acute cholestasis in mice.
authors.affiliation: Leiden Academic Centre for Drug Research, The Netherlands. Electronic address: r.van.der.geest@lacdr.leidenuniv.nl.
authors.forename: Rick
authors.initials: R
authors.lastname: van der Geest
authors.affiliation: Leiden Academic Centre for Drug Research, The Netherlands. Electronic address: a.b.ouweneel@lacdr.leidenuniv.nl.
authors.forename: Amber B
authors.initials: AB
authors.lastname: Ouweneel
authors.affiliation: Leiden Academic Centre for Drug Research, The Netherlands. Electronic address: r.vandersluis@lacdr.leidenuniv.nl.
authors.forename: Ronald J
authors.initials: RJ
authors.lastname: van der Sluis
authors.affiliation: University Medical Center Groningen, The Netherlands. Electronic address: a.k.groen@umcg.nl.
authors.forename: Albert K
authors.initials: AK
authors.lastname: Groen
authors.affiliation: Leiden Academic Centre for Drug Research, The Netherlands. Electronic address: m.eck@lacdr.leidenuniv.nl.
authors.forename: Miranda
authors.initials: M
authors.lastname: Van Eck
authors.affiliation: Leiden Academic Centre for Drug Research, The Netherlands. Electronic address: hoekstra@lacdr.leidenuniv.nl.
authors.forename: Menno
authors.initials: M
authors.lastname: Hoekstra
mesh_terms: D015058:1-Naphthylisothiocyanate; D000315:Adrenalectomy; D000818:Animals; D001647:Bile Acids and Salts / Q000378:metabolism; D002779:Cholestasis / Q000097:blood* / Q000139:chemically induced / Q000150:complications / Q000378:metabolism / Q000473:pathology; D002784:Cholesterol / Q000097:blood; D003345:Corticosterone / Q000097:blood*; D006937:Hypercholesterolemia / Q000097:blood* / Q000209:etiology / Q000378:metabolism / Q000473:pathology; D008099:Liver / Q000378:metabolism / Q000473:pathology; D008107:Liver Diseases / Q000097:blood* / Q000209:etiology / Q000378:metabolism / Q000473:pathology; D008810:Mice, Inbred C57BL; D015735:Mifepristone / Q000494:pharmacology; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics; D011965:Receptors, Glucocorticoid / Q000037:antagonists & inhibitors; D000099150:Receptor, Farnesoid X-Activated
chemical_list: D015058:1-Naphthylisothiocyanate; D001647:Bile Acids and Salts; D002784:Cholesterol; D003345:Corticosterone; D015735:Mifepristone; D018160:Receptors, Cytoplasmic and Nuclear; D011965:Receptors, Glucocorticoid; D000099150:Receptor, Farnesoid X-Activated
keywords: Adrenalectomy; Cholestatic liver disease; Experimental mouse model; Glucocorticoids; Hypercholesterolemia; RU-486