Nuclear receptors are ligand-modulated transcription factors. On the basis of the completed human genome sequence, this family was thought to contain 48 functional members. However, by mining human and mouse genomic sequences, we identified FXR␤ as a novel family member. It is a functional receptor in mice, rats, rabbits, and dogs but constitutes a pseudogene in humans and primates. Murine FXR␤ is widely coexpressed with FXR in embryonic and adult tissues. It heterodimerizes with RXR␣ and stimulates transcription through specific DNA response elements upon addition of 9-cis-retinoic acid. Finally, we identified lanosterol as a candidate endogenous ligand that induces coactivator recruitment and transcriptional activation by mFXR␤. Lanosterol is an intermediate of cholesterol biosynthesis, which suggests a direct role in the control of cholesterol biosynthesis in nonprimates. The identification of FXR␤ as a novel functional receptor in nonprimate animals sheds new light on the species differences in cholesterol metabolism and has strong implications for the interpretation of genetic and pharmacological studies of FXR-directed physiologies and drug discovery programs.Cholesterol metabolism is a tightly regulated enzymatic pathway. Deregulation of this pathway leads to accumulation of excess cholesterol and can result in diseases such as atherosclerosis and gallstone formation (10). The homeostatic balance between uptake and elimination of cholesterol is accomplished by regulation of three pathways: de novo cholesterol synthesis from acetate, uptake of cholesterol from the intestine, and elimination of cholesterol through the synthesis of bile acids.Cholesterol catabolism into bile acids is controlled by transcriptional feedback and feedforward mechanisms that are mediated by members of the nuclear receptor family. Activation of cholesterol breakdown into bile acids is mediated by liver X receptor alpha (LXR␣; NR1H3), a nuclear receptor that binds oxysterols formed during the synthesis and metabolism of cholesterol (14,18,28). Together with another nuclear receptor, liver receptor homologue 1 (NR5A2), LXR␣ stimulates transcription of cholesterol 7␣-hydroxylase (CYP7A1), an enzyme catalyzing the rate-limiting step of this pathway. Suppression of cholesterol degradation into bile acids is triggered by the farnesoid X receptor (FXR; NR1H4), which binds to and is activated by bile acids (21, 27, 33). Ligand-bound FXR activates transcription of the short heterodimer partner (NR0B2) and subsequently downregulates transcription of CYP7A1 (11, 19). However, there are species differences in the regulation of cholesterol metabolism and sensitivity to dietary cholesterol. While rodents respond to cholesterol feeding with induction of CYP7A1, humans and rabbits appear to lack this response and are left more sensitive to the cholesterolemic effects of dietary cholesterol (13,35,36). This difference was directly attributed to the ability of LXR to regulate CYP7A in different species (4, 24).Nuclear hormone receptors form a famil...

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Removal of the posterior pituitary from anesthetized male rats results in a prompt and significant increase in circulating prolactin that is reversed by the injection of dopamine. Posterior pituitary extracts, which contain high concentrations of endogenous dopamine, inhibit prolactin secretion from isolated anterior pituitary cells. This inhibition is prevented by incubation of the cells with the dopamine receptor antagonist (+)-butaclamol. The data show that posterior pituitary dopamine reaches the anterior pituitary via the short hypophysial portal vessels and participates in the regulation of prolactin secretion.

To assess whether gonadotropin-releasing hormone (GnRH) release from the hypothalamus might be altered by hyperprolactinemia in the male rat, we measured in chronically hyperprolactinemic rats the pituitary GnRH receptor content and described the pattern of luteinizing hormone (LH) release during the postcastration rise in gonadotropin secretion 24 and 72 h after gonadectomy. In intact rats, the effect of hyperprolactinemia was determined by describing the pattern of LH secretion, pituitary GnRH receptor content and assessment of pituitary responsiveness to small doses of GnRH (1.0 ng). In addition, to determine the role endogenous opioids might play in inhibiting GnRH release in hyperprolactinemic rats, we examined the effect of both a continuous infusion and a bolus injection of the opioid antagonist naloxone on the pattern of LH release. Chronic hyperprolactinemia was achieved by implanting 4 pituitaries under the kidney capsules 3–4 weeks before study. Acute hyperprolactinemia was achieved by injecting rats with 1 mg ovine prolactin every 12 h for 3 days. Control animals were untreated or were chronically hyperprolactinemic rats in which the hyperprolactinemia was transiently reversed by treatment for 3 days with the dopamine agonist 2-α-bromoergocryptine. The mean LH concentration was greatly decreased at 24 postcastration in chronically hyperprolactinemic rats relative to controls. This decrease was associated with a decrease in LH pulse height and pulse amplitude and pituitary GnRH receptor content, but not with an increase in the LH interpulse interval. In contrast, the decrease in mean LH concentrations in hyperprolactinemic animals at 72 h postcastration was primarily associated with a significantly longer LH interpulse interval than that observed in control animals. Chronic hyperprolactinemia in intact rats decreased the pituitary GnRH receptor content, in addition to decreasing the mean LH concentrations during pulsatile GnRH administration. Chronic hyperprolactinemia also inhibited LH release relative to controls during the continuous 4-hour infusion of naloxone and in response to a bolus injection of naloxone. However, in acutely hyperprolactinemic intact male rats a bolus injection of naloxone increased LH secretion 20 min later to levels similar to those obtained in control rats. In summary, these results indicate that chronic hyperprolactinemia decreased LH secretion by primarily decreasing GnRH secretion as suggested by a decrease in pituitary GnRH receptor content and a decrease in LH pulse frequency and pulse amplitude. It is also possible that a decrease in pituitary responsiveness to GnRH may have contributed to the decrease in LH pulse amplitude. The effects of chronic hyperprolactinemia do not appear to be mediated by an opioid whose actions are antagonized by naloxone.

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