Multihormonal regulation of hepatic sinusoidal Ntcp gene expression.
Bile acids are efficiently removed from sinusoidal blood by a number of transporters including the Na+-taurocholate-cotransporting polypeptide (Ntcp). Na+-dependent bile salt uptake, as well as Ntcp, are expressed twofold higher in male compared with female rat livers. Also, estrogen administration to male rats decreases Ntcp expression. The aims of this study were to determine the hormonal mechanism(s) responsible for this sexually dimorphic expression of Ntcp. We examined castrated and hypophysectomized rats of both sexes. Sex steroid hormones, growth hormone, thyroid, and glucocorticoids were administered, and livers were examined for changes in Ntcp messenger RNA (mRNA). Ntcp mRNA and protein content were selectively increased in males. Estradiol selectively decreased Ntcp expression in males, whereas ovariectomy increased Ntcp in females, confirming the importance of estrogens in regulating Ntcp. Hypophysectomy decreased Ntcp mRNA levels in males and prevented estrogen administration from decreasing Ntcp, indicating the importance of pituitary hormones. Although constant infusion of growth hormone to intact males reduced Ntcp, its replacement alone after hypophysectomy did not restore the sex differences. In contrast, thyroid hormone and corticosterone increased Ntcp mRNA in hypophysectomized rats. Sex differences in Ntcp mRNA levels were produced only when the female pattern of growth hormone was administered to animals also receiving thyroid and corticosterone. Thyroid and dexamethasone also increased Ntcp mRNA in isolated rat hepatocytes, whereas growth hormone decreased Ntcp. These findings demonstrate the essential role that pituitary hormones play in the sexually dimorphic control of Ntcp expression in adult rat liver and in the mediation of estrogen effects.
Simon
Francis R
FR
Univ. of Colorado Health Sciences Center, Dept. of Medicine B-145 4200 E. 9th Ave., Denver, CO 80262, USA. franz.simon@uchsc.edu
Fortune
John
J
Iwahashi
Mieko
M
Qadri
Ishtiaq
I
Sutherland
Eileen
E
D000074020:ATP Binding Cassette Transporter, Subfamily B, Member 11; D018528:ATP-Binding Cassette Transporters / Q000235:genetics; D000728:Androgens / Q000494:pharmacology; D000818:Animals; D002352:Carrier Proteins / Q000235:genetics*; D003345:Corticosterone / Q000494:pharmacology; D004958:Estradiol / Q000494:pharmacology; D005260:Female; D015870:Gene Expression / Q000187:drug effects / Q000502:physiology; D013006:Growth Hormone / Q000494:pharmacology; D006728:Hormones / Q000494:pharmacology*; D008099:Liver / Q000502:physiology*; D008297:Male; D026901:Membrane Transport Proteins; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000235:genetics; D029363:Organic Anion Transporters, Sodium-Dependent; D010902:Pituitary Gland / Q000502:physiology; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D017207:Rats, Sprague-Dawley; D012727:Sex Characteristics; D027981:Symporters; D013739:Testosterone / Q000494:pharmacology; D013974:Thyroxine / Q000494:pharmacology
D000074020:ATP Binding Cassette Transporter, Subfamily B, Member 11; D018528:ATP-Binding Cassette Transporters; D000728:Androgens; D002352:Carrier Proteins; D003345:Corticosterone; D004958:Estradiol; D013006:Growth Hormone; D006728:Hormones; D026901:Membrane Transport Proteins; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D029363:Organic Anion Transporters, Sodium-Dependent; D012333:RNA, Messenger; D027981:Symporters; D013739:Testosterone; D013974:Thyroxine; C490548:Abcb11 protein, rat; C071908:sodium-bile acid cotransporter; C114462:multidrug resistance-associated protein 3