Loss of Sexually Dimorphic Liver Gene Expression upon Hepatocyte-Specific Deletion of Stat5a-Stat5b Locus

Holloway, Minita G.; Cui, Yongzhi; Laz, Ekaterina V.; Hosui, Atsushi; Hennighausen, Lothar; Waxman, David J.

doi:10.1210/en.2006-1419

Cited by 104 publications

(119 citation statements)

References 42 publications

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“…The downstream elements of this sex-bias mechanism are male versus female patterned secretion of GHRH from the hypothalamus into the hypophyseal portal circulation and then corresponding patterned secretion of GH by the pituitary into the general circulation. This finding was discovered by Edén in 1979 (55) and, since then, has been extensively confirmed in mice, rats and humans (27,(45)(46)(47)(48)(49)(50)(56)(57)(58)(59)(60)(61)(62). Circulating GH levels in the male (M) are usually called "pulsatile" (two to four peaks per day) with very low interpulse levels; in the female (F), there is a higher frequency of pulses (seven or more peaks per day) with significant interpulse levels; thus, this is called "more continuous" (Figures 1, 2).…”

Section: A Gap In Knowledge In the Ph Literature Concerning Sex Bias supporting

confidence: 52%

“…Circulating GH levels in the male (M) are usually called "pulsatile" (two to four peaks per day) with very low interpulse levels; in the female (F), there is a higher frequency of pulses (seven or more peaks per day) with significant interpulse levels; thus, this is called "more continuous" (Figures 1, 2). This scenario results in M versus F patterned activation of PY-STAT5a/b in the distal tissues and, downstream of that, a major cascade of sex-biased gene expression of >1,000 genes ( Figure 3) (27,(41)(42)(43)(44)(45)(46)(47)(48). Even when as- Figure 2.…”

Section: A Gap In Knowledge In the Ph Literature Concerning Sex Bias mentioning

confidence: 99%

“…However, it was shown in 1973 by Colby et al (32), and extensively confirmed by numerous studies since then (27,(33)(34)(35)(36)(37)(38)(39)(40)(41)(42)(43), that the feminizing effect on sex-biased liver gene expression of an injection of E2 into a rat or mouse was indirect and had an absolute dependence on the pituitary ( Figure 1). As explained in detail by Waxman and colleagues over the last 2 decades, this neuroendocrine mechanism of sex bias, working through an axis consisting of the hypothalamic arcuate nucleus-growth hormone releasing hormone (GHRH)-growth hormone (GH)-signal transducer and activator of transcription 5 (STAT5) accounts for sex-biased expression of >1,000 genes in the liver and also of body growth and body weight (27,(41)(42)(43)(44)(45)(46)(47)(48) (Figures 2, 3). Parenthetically, STAT5 is the major transcription factor activated by the binding of GH to its receptor on all cell types (27,(41)(42)(43)(44)(45)(46)(47)(48).…”

Section: A Gap In Knowledge In the Ph Literature Concerning Sex Bias mentioning

confidence: 99%

“…As explained in detail by Waxman and colleagues over the last 2 decades, this neuroendocrine mechanism of sex bias, working through an axis consisting of the hypothalamic arcuate nucleus-growth hormone releasing hormone (GHRH)-growth hormone (GH)-signal transducer and activator of transcription 5 (STAT5) accounts for sex-biased expression of >1,000 genes in the liver and also of body growth and body weight (27,(41)(42)(43)(44)(45)(46)(47)(48) (Figures 2, 3). Parenthetically, STAT5 is the major transcription factor activated by the binding of GH to its receptor on all cell types (27,(41)(42)(43)(44)(45)(46)(47)(48). This activation involves Tyr phosphorylation of receptor-associated Janus kinases, with the latter then mediating Tyr phosphorylation of STAT5.…”

Section: A Gap In Knowledge In the Ph Literature Concerning Sex Bias mentioning

confidence: 99%

“…Thus, much of the biological activity of GH on different cell types is mediated by this activation of STAT5. From among the family of STAT transcription factors, STAT5a and STAT5b are the only transcription factors that mediate sex bias (27,(41)(42)(43)(44)(45)(46)(47)(48).…”

Section: A Gap In Knowledge In the Ph Literature Concerning Sex Bias mentioning

confidence: 99%

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Hypothesis: Neuroendocrine Mechanisms (Hypothalamus-Growth Hormone-STAT5 Axis) Contribute to Sex Bias in Pulmonary Hypertension

Sehgal

Yang

Miller

2015

Mol Med

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Pulmonary hypertension (PH) is a disease with high morbidity and mortality. The prevalence of idiopathic pulmonary arterial hypertension (IPAH) and hereditary pulmonary arterial hypertension (HPAH) is approximately two-to four-fold higher in women than in men. Paradoxically, there is an opposite male bias in typical rodent models of PH (chronic hypoxia or monocrotaline); in these models, administration of estrogenic compounds (for example, estradiol-17β [E2]) is protective. Further complexities are observed in humans ingesting anorexigens (female bias) and in rodent models, such as after hypoxia plus SU5416/Sugen (little sex bias) or involving serotonin transporter overexpression or dexfenfluramine administration (female bias). These complexities in sex bias in PH remain incompletely understood. We recently discovered that conditional deletion of signal transducer and activator of transcription 5a/b (STAT5a/b) in vascular smooth muscle cells abrogated the male bias in PH in hypoxic mice and that late-stage obliterative lesions in patients of both sexes with IPAH and HPAH showed reduced STAT5a/b, reduced Tyr-P-STAT5 and reduced B-cell lymphoma 6 protein (BCL6). In trying to understand the significance of these observations, we realized that there existed a wellcharacterized E2-sensitive central neuroendocrine mechanism of sex bias, studied over the last 40 years, that, at its peripheral end, culminated in species-specific male ("pulsatile") versus female ("more continuous") temporal patterns of circulating growth hormone (GH) levels leading to male versus female patterned activation of STAT5a/b in peripheral tissues and thus sex-biased expression of hundreds of genes. In this report, we consider the contribution of this neuroendocrine mechanism (hypothalamus-GH-STAT5) in the generation of sex bias in different PH situations.

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Section: A Gap In Knowledge In the Ph Literature Concerning Sex Bias supporting

confidence: 52%

Section: A Gap In Knowledge In the Ph Literature Concerning Sex Bias mentioning

confidence: 99%

Section: A Gap In Knowledge In the Ph Literature Concerning Sex Bias mentioning

confidence: 99%

Section: A Gap In Knowledge In the Ph Literature Concerning Sex Bias mentioning

confidence: 99%

Section: A Gap In Knowledge In the Ph Literature Concerning Sex Bias mentioning

confidence: 99%

See 3 more Smart Citations

Hypothesis: Neuroendocrine Mechanisms (Hypothalamus-Growth Hormone-STAT5 Axis) Contribute to Sex Bias in Pulmonary Hypertension

Sehgal

Yang

Miller

2015

Mol Med

View full text Add to dashboard Cite

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Sex Differences in Drug Metabolism

Chang

Waxman

2012

Encyclopedia of Drug Metabolism and Interactions

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Sex differences in drug metabolism are recognized as a major determinant of sex differences in pharmacokinetics and an important contributor to interindividual differences in drug metabolism and, in some cases, drug action. Sex differences in human drug metabolism have also been observed with a variety of drugs. The biochemical basis of sex differences in hepatic drug metabolism was largely unknown until the 1980s when it was discovered that the expression of many drug‐metabolizing enzymes, including several members of the cytochrome P450 (CYP) superfamily, is sex dependent in rat and mouse liver. Well‐studied examples include rat enzymes CYP2C11, which is male specific in its expression, and CYP2C12 (female specific) and CYP2A1 (female predominant). The major gonadal hormones, testosterone and estradiol, regulate the sex‐dependent expression of rat hepatic CYP enzymes indirectly, through their effects on the hypothalamus and its regulation of the sexually dimorphic, ultradian rhythm of pituitary growth hormone (GH) secretion, which ultimately dictates the sex‐dependent patterns of expression of these CYPs and certain other drug‐metabolizing enzymes. In male rats, the intermittent, pulsatile pattern of GH secretion stimulates the expression of male‐specific liver enzymes, whereas the more continuous pattern of GH release in females suppresses the expression male‐specific enzymes while inducing female‐specific enzymes. The current view is that the transcription factors STAT5b and HNF4α coordinately regulate the action of GH and its resultant effect on the sex‐dependent expression of hepatic CYP genes and thus provide a molecular basis for sex differences in drug metabolism.

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