{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,20]],"date-time":"2026-07-20T14:21:10Z","timestamp":1784557270116,"version":"3.55.0"},"reference-count":100,"publisher":"Bioscientifica","issue":"2","content-domain":{"domain":["joe.bioscientifica.com"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2019,8]]},"abstract":"\n Chronic glucocorticoid overexposure predisposes to the development of atherosclerotic cardiovascular disease in humans. Cholestatic liver disease is associated with increased plasma glucocorticoid levels. Here, we determined \u2013 in a preclinical setting \u2013 whether the chronic presence of cholestatic liver disease also induces a concomitant negative impact on atherosclerosis susceptibility. Hereto, regular chow diet-fed atherosclerosis-susceptible hypercholesterolemic apolipoprotein E (APOE)-knockout mice were treated with the bile duct toxicant alpha-naphthylisothiocyanate (ANIT) for 8 weeks. ANIT exposure induced the development of fibrotic cholestatic liver disease as evident from collagen deposits and compensatory bile duct hyperproliferation within the liver and the rise in plasma levels of bilirubin (+60%;\n P<\/jats:italic>\n \u2009<\u20090.01) and bile acids (10-fold higher;\n P<\/jats:italic>\n \u2009<\u20090.01). Adrenal weights (+22%;\n P<\/jats:italic>\n \u2009<\u20090.01) and plasma corticosterone levels (+72%;\n P<\/jats:italic>\n \u2009<\u20090.01) were increased in ANIT-treated mice. In contrast, atherosclerosis susceptibility was not increased in response to ANIT feeding, despite the concomitant increase in plasma free cholesterol (+30%;\n P<\/jats:italic>\n \u2009<\u20090.01) and cholesteryl ester (+42%;\n P<\/jats:italic>\n \u2009<\u20090.001) levels. The ANIT-induced hypercorticosteronemia coincided with marked immunosuppression as judged from the 50% reduction (\n P<\/jats:italic>\n \u2009<\u20090.001) in circulating lymphocyte numbers. However, hepatic glucocorticoid signaling was not enhanced after ANIT treatment. It thus appears that the immunosuppressive effect of glucocorticoids is uncoupled from their metabolic effect under cholestatic disease conditions. In conclusion, we have shown that cholestatic liver disease-associated endogenous glucocorticoid overexposure does not increase atherosclerosis susceptibility in APOE-knockout mice. Our studies provide novel preclinical evidence for the observations that the hypercholesterolemia seen in cholestatic human subjects does not translate into a higher risk for atherosclerotic cardiovascular disease.\n <\/jats:p>","DOI":"10.1530\/joe-19-0079","type":"journal-article","created":{"date-parts":[[2019,4,29]],"date-time":"2019-04-29T12:03:40Z","timestamp":1556539420000},"page":"1-12","update-policy":"https:\/\/doi.org\/10.1530\/crossmarkpolicy-5","source":"Crossref","is-referenced-by-count":1,"title":["Cholestasis-associated glucocorticoid overexposure does not increase atherogenesis"],"prefix":"10.1530","volume":"242","author":[{"given":"Rick","family":"van der Geest","sequence":"first","affiliation":[{"name":"1Division of BioTherapeutics, Leiden Academic Centre for Drug Research, Gorlaeus Laboratories, Leiden, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ronald J","family":"van der Sluis","sequence":"additional","affiliation":[{"name":"1Division of BioTherapeutics, Leiden Academic Centre for Drug Research, Gorlaeus Laboratories, Leiden, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Albert K","family":"Groen","sequence":"additional","affiliation":[{"name":"2Departments of Pediatrics and Laboratory Medicine, University Medical Center Groningen, Groningen, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Miranda","family":"Van Eck","sequence":"additional","affiliation":[{"name":"1Division of BioTherapeutics, Leiden Academic Centre for Drug Research, Gorlaeus Laboratories, Leiden, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Menno","family":"Hoekstra","sequence":"additional","affiliation":[{"name":"1Division of BioTherapeutics, Leiden Academic Centre for Drug Research, Gorlaeus Laboratories, Leiden, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"416","reference":[{"key":"ref101","doi-asserted-by":"crossref","first-page":"1993","DOI":"10.1001\/jama.2009.1619","article-title":"Major lipids, apolipoproteins, and risk of vascular disease","volume":"302","year":"2009","journal-title":"JAMA"},{"key":"ref201","doi-asserted-by":"crossref","first-page":"738","DOI":"10.1194\/jlr.M700475-JLR200","article-title":"Absence of HDL cholesteryl ester uptake in mice via SR-BI impairs an adequate adrenal glucocorticoid-mediated stress response to fasting","volume":"49","year":"2008","journal-title":"Journal of Lipid Research"},{"key":"ref371","doi-asserted-by":"crossref","first-page":"1289","DOI":"10.1053\/jhep.2000.20525","article-title":"Endotoxin-induced mortality in bile duct-ligated rats after administration of reconstituted high-density lipoprotein","volume":"32","year":"2000","journal-title":"Hepatology"},{"key":"ref151","doi-asserted-by":"crossref","first-page":"167","DOI":"10.1016\/S0166-4328(03)00188-8","article-title":"Increased corticosterone secretion and early-onset of cognitive decline in female apolipoprotein E-knockout mice","volume":"148","year":"2004","journal-title":"Behavioural Brain Research"},{"key":"ref21","doi-asserted-by":"crossref","first-page":"263","DOI":"10.1111\/liv.12680","article-title":"Serum metabolic signatures of primary biliary cirrhosis and primary sclerosing cholangitis","volume":"35","year":"2015","journal-title":"Liver International"},{"key":"ref711","doi-asserted-by":"crossref","first-page":"1039","DOI":"10.1194\/jlr.M800410-JLR200","article-title":"Scavenger receptor class B type I-mediated uptake of serum cholesterol is essential for optimal adrenal glucocorticoid production","volume":"50","year":"2009","journal-title":"Journal of Lipid Research"},{"key":"ref951","doi-asserted-by":"crossref","first-page":"77","DOI":"10.3109\/00365529709025067","article-title":"Primary biliary cirrhosis in the Netherlands. 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