Transcriptional regulation of hepatic sterol 27-hydroxylase by bile acids

1996 ◽  
Vol 270 (4) ◽  
pp. G646-G652 ◽  
Author(s):  
Z. R. Vlahcevic ◽  
S. K. Jairath ◽  
D. M. Heuman ◽  
R. T. Stravitz ◽  
P. B. Hylemon ◽  
...  
Keyword(s):  
Bile Acid ◽  
Bile Acids ◽  
Specific Activity ◽  
Feedback Regulation ◽  
Initial Step ◽  
Mrna Levels ◽  
Acid Biosynthesis ◽  
Negative Feedback Regulation ◽  
Study Objective ◽  
Specific Activities

The study objective was to determine whether and to what extent sterol 27-hydroxylase, the initial step in the "acidic" pathway of bile acid biosynthesis, is regulated by bile acids. Rats were fed diets supplemented with cholestyramine (CT, 5%), cholate (CA, 1%), chenodeoxycholate (CDCA, 1%), or deoxycholate (DCA, 0.25%). When compared with paired controls, sterol 27-hydroxylase and cholesterol 7 alpha-hydroxylase specific activities increased after CT administration by 188 +/- 20% (P < 0.05) and 415 +/- 36% (P < 0.01), respectively. Similarly, mRNA levels increased by 159 +/- 14% (P < 0.05) and 311 +/- 106% (P < 0.05), respectively. Feeding CA, CDCA, or DCA decreased sterol 27-hydroxylase specific activity to 57 +/- 6, 61 +/- 8, and 74 +/- 8% of controls, respectively (P < 0.05). By comparison, the specific activity of cholesterol 7 alpha-hydroxylase decreased to 46 +/- 7 , 32 +/- 10, and 26 +/- 8% (P = 0.001). mRNA levels and transcriptional activities for sterol 27-hydroxylase and cholesterol 7 alpha-hydroxylase transcriptional activity were changed to the same extent as the specific activities after CT or bile acid feeding. We conclude that sterol 27-hydroxylase and cholesterol 7 alpha-hydroxylase are subject to negative feedback regulation by hydrophobic bile acids at the level of transcription. However, the responses of sterol 27-hydroxylase to manipulation of the bile acid pool are less prominent than those of cholesterol 7 alpha-hydroxylase. During the diurnal cycle the specific activities of sterol 27-hydroxylase and cholesterol 7 alpha-hydroxylase changed in tandem, suggesting that both may be under control of glucocorticoids.

Development of enzymatic conjugation and sulfation of bile acids in hamster liver

1980 ◽  
Vol 238 (5) ◽  
pp. G429-G433
Author(s):  
J. T. Jordan ◽  
P. G. Killenberg
Keyword(s):  
Enzyme Activity ◽  
Bile Acid ◽  
Bile Acids ◽  
Postnatal Development ◽  
Early Development ◽  
Specific Activity ◽  
Specific Activities

In vitro levels of enzyme activity were measured in liver from fetal and developing hamsters to study the fetal immaturity and postnatal development of bile acid conjugation and sulfation. Sulfation and conjugation were measured in the same animals. Partial reactions of bile acid conjugation were assayed independently; sulfation of conjugated and unconjugated lithocholate was measured separately. From 3 days before to 3 days after birth, specific activity for sulfation of lithocholate and lithocholate conjugates was similar; lithocholate sulfation was 80% of adult levels. In older hamsters, specific activity for sulfation of lithocholate conjugates was significantly higher than that for lithocholate. Specific activities of both partial reactions of bile acid conjugation were 12% of adult levels from 3 days before to 3 days after birth. Thereafter both activities increased together; the ratio of glycine to taurine-dependent conjugation was similar at all ages. The data suggest early development of a separate mechanism for lithocholate sulfation. Enzymes catalyzing bile acid conjugation and sulfation of bile acid conjugates exhibit maximal development after birth.

The nuclear receptor for bile acids, FXR, transactivates human organic solute transporter-α and -β genes

2006 ◽  
Vol 290 (3) ◽  
pp. G476-G485 ◽  
Author(s):  
Jean-François Landrier ◽  
Jyrki J. Eloranta ◽  
Stephan R. Vavricka ◽  
Gerd A. Kullak-Ublick
Keyword(s):  
Bile Acid ◽  
Bile Acids ◽  
Cultured Cells ◽  
Farnesoid X Receptor ◽  
Mrna Levels ◽  
Small Interfering Rnas ◽  
Organic Solute Transporter ◽  
Genes Encoding ◽  
Organic Solute ◽  
Solute Transporter

Bile acids are synthesized from cholesterol in the liver and are excreted into bile via the hepatocyte canalicular bile salt export pump. After their passage into the intestine, bile acids are reabsorbed in the ileum by sodium-dependent uptake across the apical membrane of enterocytes. At the basolateral domain of ileal enterocytes, bile acids are extruded into portal blood by the heterodimeric organic solute transporter OSTα/OSTβ. Although the transport function of OSTα/OSTβ has been characterized, little is known about the regulation of its expression. We show here that human OSTα/OSTβ expression is induced by bile acids through ligand-dependent transactivation of both OST genes by the nuclear bile acid receptor/farnesoid X receptor (FXR). FXR agonists induced endogenous mRNA levels of OSTα and OSTβ in cultured cells, an effect that was not discernible upon inhibition of FXR expression by small interfering RNAs. Furthermore, OST mRNAs were induced in human ileal biopsies exposed to the bile acid chenodeoxycholic acid. Reporter constructs containing OSTα or OSTβ promoters were transactivated by FXR in the presence of its ligand. Two functional FXR binding motifs were identified in the OSTα gene and one in the OSTβ gene. Targeted mutation of these elements led to reduced inducibility of both OST promoters by FXR. In conclusion, the genes encoding the human OSTα/OSTβ complex are induced by bile acids and FXR. By coordinated control of OSTα/OSTβ expression, bile acids may adjust the rate of their own efflux from enterocytes in response to changes in intracellular bile acid levels.

scholarly journals Ontogeny of pituitary thyrotrophs and regulation by endogenous thyroid hormone feedback in the chick embryo

2005 ◽  
Vol 184 (2) ◽  
pp. 407-416 ◽  
Author(s):  
Michael Muchow ◽  
Ioannis Bossis ◽  
Tom E Porter
Keyword(s):  
Thyroid Hormone ◽  
Thyroid Hormones ◽  
Anterior Pituitary ◽  
Feedback Regulation ◽  
Thyroid Stimulating Hormone ◽  
Mrna Levels ◽  
Hormone Production ◽  
Negative Feedback Regulation ◽  
Cephalic Lobe ◽  
Whole Mount

Increased thyroid hormone production is essential for hatching of the chick and for the increased metabolism necessary for posthatch endothermic life. However, little is known about the ontogeny and distribution of pituitary thyrotrophs during this period or whether pituitary thyroid-stimulating hormone (TSH) production is regulated by endogenous thyroid hormones during chick embryonic development. This study assessed the abundance and location of pituitary thyrotrophs and the regulation of TSHβ peptide and mRNA levels by endogenous thyroid hormones prior to hatching. TSHβ-containing cells were first detected on embryonic day (e) 11, and the thyrotroph population increased to maximum levels on e17 and e19 and then decreased prior to hatching (d1). Thyrotroph distribution within the cephalic lobe of the anterior pituitary was determined on e19 by whole-mount immunocytochemistry for TSHβ peptide and by whole-mount in situ hybridization for TSHβ mRNA. Thyrotroph distribution within the cephalic lobe was heterogeneous among embryos, but most commonly extended from the ventral medial region to the dorsal lateral regions, along the boundary of the cephalic and caudal lobes. Inhibition of endogenous thyroid hormone production with methi-mazole (MMI) decreased plasma thyroxine (T4) levels and increased pituitary TSHβ mRNA levels on e19 and d1. However, control pituitaries contained significantly more TSHβ peptide than MMI-treated pituitaries on e17 and e19, suggesting higher TSH secretion into the blood in MMI-treated groups. We conclude that thyrotroph abundance and TSH production increase prior to hatching, that thyrotrophs are localized heterogenenously within the cephalic lobe of the anterior pituitary at that time, and that TSH gene expression and secretion are under negative feedback regulation from thyroid hormones during this critical period of development.

Regulation of the mouse organic solute transporter α-β, Ostα-Ostβ, by bile acids

2006 ◽  
Vol 290 (5) ◽  
pp. G912-G922 ◽  
Author(s):  
Tamara Frankenberg ◽  
Anuradha Rao ◽  
Frank Chen ◽  
Jamie Haywood ◽  
Benjamin L. Shneider ◽  
...  
Keyword(s):  
Bile Acid ◽  
Bile Acids ◽  
Promoter Activity ◽  
Colon Adenocarcinoma ◽  
Dominant Negative ◽  
Farnesoid X Receptor ◽  
Negative Feedback Regulation ◽  
Organic Solute Transporter ◽  
Organic Solute ◽  
Solute Transporter

The mechanisms responsible for bile acid regulation of mouse intestinal organic solute transporter α-β (Ostα-Ostβ) expression were investigated. Expression of Ostα-Ostβ mRNA was increased in cecum and proximal colon of cholic acid-fed mice and in chenodeoxycholate-treated mouse CT26 colon adenocarcinoma cells. Sequence analysis revealed potential cis-acting elements for farnesoid X receptor (FXR) and liver receptor homolog-1 (LRH-1) in the mouse Ostα and Ostβ promoters and reporter constructs containing Ostα and Ostβ 5′-flanking sequences were positively regulated by bile acids. Expression of a dominant-negative FXR, reduction of FXR with interfering small RNA (siRNA), or mutation of the potential FXR elements decreased Ostα and Ostβ promoter activity and abolished the induction by chenodeoxycolic acid. Negative regulation of the Ostα and Ostβ promoters by bile acids was mediated through LRH-1 elements. Ostα and Ostβ promoter activities were increased by coexpression of LRH-1 and decreased by coexpression of SHP. Mutation of the potential LRH-1 elements and siRNA-mediated reduction of LRH-1 expression decreased basal promoter activity. As predicted from the promoter analyses, ileal Ostα and Ostβ mRNA expressions were increased in wild-type mice administered the FXR agonist GW4064 and decreased in FXR-null mice. Immunoblotting analysis revealed that Ostα and Ostβ intestinal protein expressions correlated with mRNA expression. The mouse Ostα and Ostβ promoters are unusual in that they contain functional FXR and LRH elements, which mediate, respectively, positive and negative feedback regulation by bile acids. Although the positive regulatory pathway appears to be dominant, this arrangement provides a mechanism to finely titrate Ostα-Ostβ expression to the bile acid flux.

scholarly journals Bile acid-induced negative feedback regulation of the human ileal bile acid transporter

Hepatology ◽  
2004 ◽  
Vol 40 (1) ◽  
pp. 149-156 ◽  
Author(s):  
Ezequiel Neimark ◽  
Frank Chen ◽  
Xiaoping Li ◽  
Benjamin L. Shneider
Keyword(s):  
Bile Acid ◽  
Negative Feedback ◽  
Feedback Regulation ◽  
Negative Feedback Regulation ◽  
Bile Acid Transporter ◽  
Acid Transporter

Development of gonadal feedback regulation of gonadotropin gene expression and secretion in female rats

1992 ◽  
Vol 127 (5) ◽  
pp. 454-458 ◽  
Author(s):  
Pirjo A Pakarinen ◽  
Ilpo T Huhtaniemi
Keyword(s):  
Negative Feedback ◽  
Feedback Regulation ◽  
Female Rats ◽  
Mrna Levels ◽  
Neonatal Rats ◽  
Adult Rats ◽  
Gonadotropin Secretion ◽  
Negative Feedback Regulation ◽  
Pituitary Gonadotropin ◽  
Old Adult

The postnatal development of the gonadal negative feedback control of gonadotropins was studied in female rats. Neonatal (5-day-old) and randomly cycling young (60-day-old) and more mature (180-day-old) adult rats were ovariectomized, and half of them received Silastic implants containing the synthetic estrogen, diethylstilbestrol. The neonatal rats were killed 5, 10 or 15 days, and the adult rats 7 days after the operation. Age-matched and sham-operated animals served as controls. There were no statistically significant responses of serum LH or FSH concentrations or of the pituitary gonadotropin subunit mRNA levels to ovariectomy at any of the neonatal ages. A marked increase (p<0.01) after ovariectomy was seen in serum gonadotropins and in the cognate mRNA levels at both adult ages. In spite of the weak feedback response of the neonatal rats to ovariectomy, diethylstilbestrol suppressed the basal pituitary gonadotropin concentrations and the specific LH and FSH β-chain mRNAs (p<0.01–0.05). These results demonstrate that the gonadal negative feedback regulation of gonadotropin synthesis and secretion is not fully developed in neonatal and prepubertal female rats before 20 days of age. This is probably due to the steroidogenic quiescence of the ovaries in early life. However, the capability of the pituitary to respond to negative estrogen feedback has developed in the neonatal female, as demonstrated by the suppressive effects of diethylstilbestrol treatment on gonadotropin secretion.

scholarly journals Cholic acid mediates negative feedback regulation of bile acid synthesis in mice

2002 ◽  
Vol 110 (8) ◽  
pp. 1191-1200 ◽  
Author(s):  
Jia Li-Hawkins ◽  
Mats Gåfvels ◽  
Maria Olin ◽  
Erik G. Lund ◽  
Ulla Andersson ◽  
...  
Keyword(s):  
Bile Acid ◽  
Cholic Acid ◽  
Negative Feedback ◽  
Feedback Regulation ◽  
Acid Synthesis ◽  
Bile Acid Synthesis ◽  
Negative Feedback Regulation

scholarly journals Antagonism of the Actions of Peroxisome Proliferator-activated Receptor-α by Bile Acids

2001 ◽  
Vol 276 (50) ◽  
pp. 47154-47162 ◽  
Author(s):  
Christopher J. Sinal ◽  
Michung Yoon ◽  
Frank J. Gonzalez
Keyword(s):  
Fatty Acid ◽  
Bile Acid ◽  
Bile Acids ◽  
The Body ◽  
Peroxisome Proliferator ◽  
Acid Biosynthesis ◽  
Peroxisome Proliferator Activated Receptor ◽  
Bile Acid Biosynthesis ◽  
Genes Encoding ◽  
The Impact

The peroxisome proliferator-activated receptor-α (PPARα) is a ligand-activated transcription factor that regulates the expression of a number of genes critical for fatty acid β-oxidation. Because a number of substrates and intermediates of this metabolic pathway serve as ligand activators of this receptor, homeostatic control of fatty acid metabolism is achieved. Evidence also exists for PPARα-dependent regulation of genes encoding critical enzymes of bile acid biosynthesis. To determine whether the primary products of bile acid biosynthesis, cholic acid and chenodeoxycholic acid, were capable of modulating PPARα function, a variety ofin vivoandin vitroapproaches were utilized. Feeding a bile acid-enriched diet significantly reduced the degree of hepatomegaly and induction of target genes encoding enzymes of fatty acid β-oxidation caused by treatment with the potent PPARα ligand Wyeth-14,643. Convergent data from mechanistic studies indicate that bile acids interfere with transactivation by PPARα at least in part by impairing the recruitment of transcriptional coactivators. The results of this study provide the first evidence in favor of the existence of compounds, normally found within the body, that are capable of antagonizing the physiological actions of PPARα. The impact of PPARα antagonism by endogenous bile acids is likely to be limited under normal conditions and to have only minimal effects on bile acid homeostasis. However, during certain pathophysiological states where intracellular bile acid concentrations are elevated, meaningful effects on PPARα-dependent target gene regulation are possible.

Gonadal and sex steroid feedback regulation of gonadotrophin mRNA levels and secretion in neonatal male and female rats

1989 ◽  
Vol 3 (2) ◽  
pp. 139-144 ◽  
Author(s):  
P. Pakarinen ◽  
I. Huhtaniemi
Keyword(s):  
Sex Differences ◽  
Feedback Regulation ◽  
Female Rats ◽  
Male Rats ◽  
Sex Steroid ◽  
Mrna Levels ◽  
Negative Feedback Regulation ◽  
Α Subunit ◽  
Male And Female ◽  
Male And Female Rats

ABSTRACT Serum and pituitary LH and FSH, and their pituitary mRNA levels, were measured in neonatal male and female rats after gonadectomy and after gonadectomy with sex steroid replacement. The animals were gonadectomized on day 3 of life, and those given sex steroid replacement were implanted with silicone elastomer capsules containing testosterone for males and diethylstilboestrol for females. Shamoperated rats served as controls. The animals were killed 4 or 8 days later and the sera and pituitaries collected. Pituitary contents of mRNAs for the α subunit, FSH-β and LH-β were determined by blot hybridization using corresponding cDNAs. Distinct sex differences were found in the mRNA responses to gonadectomy and steroid replacement. In the males, gonadectomy increased all mRNA levels at 7 days of age. In the females, a rise on day 7 was detected only for FSH-β; the other mRNAs were increased on day 11 of age. The steroid replacements reversed all the post-gonadectomy increases of mRNAs in both sexes. Moreover, the common α and LH-β mRNAs of the male animals were consistently suppressed below control levels. The serum concentrations of gonadotrophins increased after gonadectomy on day 7 in the males but only on day 11 in the females. The steroid replacements also suppressed the post-gonadectomy increases in serum gonadotrophins, but only the serum concentration of FSH in the females was reduced below controls. Pituitary gonadotrophin concentrations were not affected by gonadectomy, but the steroids suppressed LH in the males and FSH in the females. It is concluded that the onset of negative-feedback regulation of gonadotrophin synthesis by gonads and/or gonadal steroids starts earlier in male rats, before 7 days of age. In female rats these responses appear between 7 and 11 days of age. Clear sex differences were observed in how gonadotrophin mRNAs and pituitary and serum hormone levels responded to gonadectomy and steroid replacement in the neonatal period. Some of the responses differed from those previously reported in adult animals.

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