title: Suppression of the HPA Axis During Cholestasis Can Be Attributed to Hypothalamic Bile Acid Signaling.
abstract: Suppression of the hypothalamic-pituitary-adrenal (HPA) axis has been shown to occur during cholestatic liver injury. Furthermore, we have demonstrated that in a model of cholestasis, serum bile acids gain entry into the brain via a leaky blood brain barrier and that hypothalamic bile acid content is increased. Therefore, the aim of the current study was to determine the effects of bile acid signaling on the HPA axis. The data presented show that HPA axis suppression during cholestatic liver injury, specifically circulating corticosterone levels and hypothalamic corticotropin releasing hormone (CRH) expression, can be attenuated by administration of the bile acid sequestrant cholestyramine. Secondly, treatment of hypothalamic neurons with various bile acids suppressed CRH expression and secretion in vitro. However, in vivo HPA axis suppression was only evident after the central injection of the bile acids taurocholic acid or glycochenodeoxycholic acid but not the other bile acids studied. Furthermore, we demonstrate that taurocholic acid and glycochenodeoxycholic acid are exerting their effects on hypothalamic CRH expression after their uptake through the apical sodium-dependent bile acid transporter and subsequent activation of the glucocorticoid receptor. Taken together with previous studies, our data support the hypothesis that during cholestatic liver injury, bile acids gain entry into the brain, are transported into neurons through the apical sodium-dependent bile acid transporter and can activate the glucocorticoid receptor to suppress the HPA axis. These data also lend themselves to the broader hypothesis that bile acids may act as central modulators of hypothalamic peptides that may be altered during liver disease.
authors.affiliation: Central Texas Veterans Health Care System 76504 (M.M., G.F., S.G., S.D.); Department of Internal Medicine (M.M., G.F., S.G., N.P., S.D.), Texas A&M Health Science Center College of Medicine 76508; Digestive Disease Research Center (M.M., G.F., S.G., S.D.) 76508; and Department of Surgery (A.D., M.K.N.-R.), Baylor Scott & White Health, Temple 76508, Texas; and Signal Transduction Laboratory (M.Q.), National Institute of Environmental Health Sciences, National Institutes of Health, Department of Health and Human Services, Research Triangle Park, North Carolina 27709.
authors.forename: Matthew
authors.initials: M
authors.lastname: McMillin
authors.affiliation: Central Texas Veterans Health Care System 76504 (M.M., G.F., S.G., S.D.); Department of Internal Medicine (M.M., G.F., S.G., N.P., S.D.), Texas A&M Health Science Center College of Medicine 76508; Digestive Disease Research Center (M.M., G.F., S.G., S.D.) 76508; and Department of Surgery (A.D., M.K.N.-R.), Baylor Scott & White Health, Temple 76508, Texas; and Signal Transduction Laboratory (M.Q.), National Institute of Environmental Health Sciences, National Institutes of Health, Department of Health and Human Services, Research Triangle Park, North Carolina 27709.
authors.forename: Gabriel
authors.initials: G
authors.lastname: Frampton
authors.affiliation: Central Texas Veterans Health Care System 76504 (M.M., G.F., S.G., S.D.); Department of Internal Medicine (M.M., G.F., S.G., N.P., S.D.), Texas A&M Health Science Center College of Medicine 76508; Digestive Disease Research Center (M.M., G.F., S.G., S.D.) 76508; and Department of Surgery (A.D., M.K.N.-R.), Baylor Scott & White Health, Temple 76508, Texas; and Signal Transduction Laboratory (M.Q.), National Institute of Environmental Health Sciences, National Institutes of Health, Department of Health and Human Services, Research Triangle Park, North Carolina 27709.
authors.forename: Matthew
authors.initials: M
authors.lastname: Quinn
authors.affiliation: Central Texas Veterans Health Care System 76504 (M.M., G.F., S.G., S.D.); Department of Internal Medicine (M.M., G.F., S.G., N.P., S.D.), Texas A&M Health Science Center College of Medicine 76508; Digestive Disease Research Center (M.M., G.F., S.G., S.D.) 76508; and Department of Surgery (A.D., M.K.N.-R.), Baylor Scott & White Health, Temple 76508, Texas; and Signal Transduction Laboratory (M.Q.), National Institute of Environmental Health Sciences, National Institutes of Health, Department of Health and Human Services, Research Triangle Park, North Carolina 27709.
authors.forename: Ali
authors.initials: A
authors.lastname: Divan
authors.affiliation: Central Texas Veterans Health Care System 76504 (M.M., G.F., S.G., S.D.); Department of Internal Medicine (M.M., G.F., S.G., N.P., S.D.), Texas A&M Health Science Center College of Medicine 76508; Digestive Disease Research Center (M.M., G.F., S.G., S.D.) 76508; and Department of Surgery (A.D., M.K.N.-R.), Baylor Scott & White Health, Temple 76508, Texas; and Signal Transduction Laboratory (M.Q.), National Institute of Environmental Health Sciences, National Institutes of Health, Department of Health and Human Services, Research Triangle Park, North Carolina 27709.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Grant
authors.affiliation: Central Texas Veterans Health Care System 76504 (M.M., G.F., S.G., S.D.); Department of Internal Medicine (M.M., G.F., S.G., N.P., S.D.), Texas A&M Health Science Center College of Medicine 76508; Digestive Disease Research Center (M.M., G.F., S.G., S.D.) 76508; and Department of Surgery (A.D., M.K.N.-R.), Baylor Scott & White Health, Temple 76508, Texas; and Signal Transduction Laboratory (M.Q.), National Institute of Environmental Health Sciences, National Institutes of Health, Department of Health and Human Services, Research Triangle Park, North Carolina 27709.
authors.forename: Nisha
authors.initials: N
authors.lastname: Patel
authors.affiliation: Central Texas Veterans Health Care System 76504 (M.M., G.F., S.G., S.D.); Department of Internal Medicine (M.M., G.F., S.G., N.P., S.D.), Texas A&M Health Science Center College of Medicine 76508; Digestive Disease Research Center (M.M., G.F., S.G., S.D.) 76508; and Department of Surgery (A.D., M.K.N.-R.), Baylor Scott & White Health, Temple 76508, Texas; and Signal Transduction Laboratory (M.Q.), National Institute of Environmental Health Sciences, National Institutes of Health, Department of Health and Human Services, Research Triangle Park, North Carolina 27709.
authors.forename: Karen
authors.initials: K
authors.lastname: Newell-Rogers
authors.affiliation: Central Texas Veterans Health Care System 76504 (M.M., G.F., S.G., S.D.); Department of Internal Medicine (M.M., G.F., S.G., N.P., S.D.), Texas A&M Health Science Center College of Medicine 76508; Digestive Disease Research Center (M.M., G.F., S.G., S.D.) 76508; and Department of Surgery (A.D., M.K.N.-R.), Baylor Scott & White Health, Temple 76508, Texas; and Signal Transduction Laboratory (M.Q.), National Institute of Environmental Health Sciences, National Institutes of Health, Department of Health and Human Services, Research Triangle Park, North Carolina 27709.
authors.forename: Sharon
authors.initials: S
authors.lastname: DeMorrow
mesh_terms: D000818:Animals; D001647:Bile Acids and Salts / Q000378:metabolism* / Q000494:pharmacology*; D002792:Cholestyramine Resin / Q000494:pharmacology; D003346:Corticotropin-Releasing Hormone / Q000378:metabolism; D007030:Hypothalamo-Hypophyseal System / Q000187:drug effects* / Q000378:metabolism*; D007031:Hypothalamus / Q000187:drug effects* / Q000378:metabolism*; D008297:Male; D010913:Pituitary-Adrenal System / Q000187:drug effects* / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D001647:Bile Acids and Salts; D002792:Cholestyramine Resin; D003346:Corticotropin-Releasing Hormone