Codependence of Growth Hormone-Responsive, Sexually Dimorphic Hepatic Gene Expression on Signal Transducer and Activator of Transcription 5b and Hepatic Nuclear Factor 4α

Holloway, Minita G.; Laz, Ekaterina V.; Waxman, David J.

doi:10.1210/me.2005-0328

Cited by 108 publications

(154 citation statements)

References 67 publications

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“…every 3.5-4 h in direct response to each plasma GH pulse in the adult male rat [16,17], raising the possibility that STAT5b-and HNF4α-stimulated transcriptional events may both be influenced by the pulsatile, male plasma-GH rhythm. This latter possibility is consistent with the sex-dependent effects that HNF4α has on certain GH-dependent hepatic genes [6,12]. In the present study, HNF4α has been shown to inhibit STAT5b transcriptional activity by blocking STAT5b tyrosine phosphorylation that is catalysed by the GH-receptor-associated tyrosine kinase JAK2.…”

Section: Discussionsupporting

confidence: 90%

“…In the present study we have characterized bi-directional crosstalk between STAT5b and HNF4α, which both play important roles in liver gene expression, in particular sex-dependent, GHregulated gene expression, as revealed by the analysis of knockout mouse models [6,12,21]. We also demonstrate that STAT5b enhances HNF4α-dependent gene transcription, while HNF4α is shown to inhibit GH-stimulated STAT5b tyrosine phosphorylation, nuclear translocation and transcriptional activity.…”

Section: Discussionmentioning

confidence: 54%

“…Further studies are required to establish the mechanism for this stimulatory effect of STAT5b and its overall importance in the regulation of HNF4α-dependent gene expression in liver. The possibility that STAT5b may play an important role in HNF4α-directed gene expression is supported by the co-dependence of several CYPs and other GHregulated, sex-specific genes on HNF4α and STAT5b that have been recently described in mouse liver [12].…”

Section: Discussionmentioning

confidence: 99%

“…HNF4α is required for the expression of certain sex-specific GHregulated liver CYP genes, several of which also require STAT5b [6,12]. We therefore investigated the possibility of signalling cross-talk between these two liver-expressed transcription factors.…”

Section: Hnf4α Inhibition Of Stat5b Tyrosine Phosphorylationmentioning

confidence: 99%

“…In particular, HNF4α was shown to determine the expression of a unique subset of mouse liver genes which differs markedly between the sexes. Notably, HNF4α was shown to positively regulate several malespecific genes whereas it negatively regulates certain femalepredominant genes through a mechanism that is operative in male, but not female, mouse liver [6,12].…”

Section: Introductionmentioning

confidence: 99%

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Signalling cross-talk between hepatocyte nuclear factor 4α and growth-hormone-activated STAT5b

Park

Wiwi

Waxman

2006

Biochemical Journal

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In the present study, we have characterized signalling cross-talk between STAT5b (signal transducer and activator of transcription 5b) and HNF4α (hepatocyte nuclear factor 4α), two major regulators of sex-dependent gene expression in the liver. In a HepG2 liver cell model, HNF4α strongly inhibited β-casein and ntcp (Na + /taurocholate cotransporting polypeptide) promoter activity stimulated by GH (growth hormone)-activated STAT5b, but had no effect on interferon-γ -stimulated STAT1 transcriptional activity. By contrast, STAT5b synergistically enhanced the transcriptional activity of HNF4α towards the ApoCIII (apolipoprotein CIII) promoter. The inhibitory effect of HNF4α on STAT5b transcription was associated with the inhibition of GH-stimulated STAT5b tyrosine phosphorylation and nuclear translocation. The short-chain fatty acid, butyrate, reversed STAT5b transcriptional inhibition by HNF4α, but did not reverse the inhibition of STAT5b tyrosine phosphorylation. HNF4α inhibition of STAT5b tyrosine phosphorylation was not reversed by pervanadate or by dominant-negative phosphotyrosine phosphatase 1B, suggesting that it does not result from an increase in STAT5b dephosphorylation. Rather, HNF4α blocked GHstimulated tyrosine phosphorylation of JAK2 (Janus kinase 2), a STAT5b tyrosine kinase. Thus STAT5b and HNF4α exhibit bidirectional cross-talk that may augment HNF4α-dependent gene transcription while inhibiting STAT5b transcriptional activity via the inhibitory effects of HNF4α on JAK2 phosphorylation, which leads to inhibition of STAT5b signalling initiated by the GH receptor at the cell surface.

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Section: Discussionsupporting

confidence: 90%

Section: Discussionmentioning

confidence: 54%

Section: Discussionmentioning

confidence: 99%

Section: Hnf4α Inhibition Of Stat5b Tyrosine Phosphorylationmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Signalling cross-talk between hepatocyte nuclear factor 4α and growth-hormone-activated STAT5b

Park

Wiwi

Waxman

2006

Biochemical Journal

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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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G‐protein‐coupled bile acid receptor plays a key role in bile acid metabolism and fasting‐induced hepatic steatosis in mice

et al. 2016

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Bile acids are signaling molecules that play a critical role in regulation of hepatic metabolic homeostasis by activating nuclear farnesoid X receptor (Fxr) and membrane G-protein-coupled receptor (Tgr5). The role of FXR in regulation of bile acid synthesis and hepatic metabolism has been studied extensively. However, the role of TGR5 in hepatic metabolism has not been explored. The liver plays a central role in lipid metabolism and impaired response to fasting and feeding contributes to steatosis and non-alcoholic fatty liver and obesity. We have performed a detailed analysis of gallbladder bile acid and lipid metabolism in Tgr5−/− mice in both free-fed and fasted conditions. Lipid profiles of serum, liver and adipose tissues, bile acid composition, energy metabolism, and mRNA and protein expression of the genes involved in lipid metabolism were analyzed. Results showed that deficiency of the Tgr5 gene in mice alleviated fasting-induced hepatic lipid accumulation. Expression of liver oxysterol 7α-hydroxylase (Cyp7b1) in the alternative bile acid synthesis pathway was reduced. Analysis of gallbladder bile acid composition showed marked increase of tauro-cholic acid and decrease of tauro-α and β-muricholic acid in Tgr5−/− mice. Tgr5−/− mice had increased hepatic fatty acid oxidation rate and decreased hepatic fatty acid uptake. Interestingly, fasting induction of fibroblast growth factor 21 (Fgf21) in liver was attenuated. In addition, fasted Tgr5−/− mice had increased activation of hepatic growth hormone-signal transducer and activator of transcription 5 (GH-Stat5) signaling compared to wild type mice. Conclusion This study suggests that TGR5 may play a role in determining bile acid composition and in fasting-induced hepatic steatosis through a novel mechanism involving activation of the GH-Stat5 signaling pathway.

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Codependence of Growth Hormone-Responsive, Sexually Dimorphic Hepatic Gene Expression on Signal Transducer and Activator of Transcription 5b and Hepatic Nuclear Factor 4α

Cited by 108 publications

References 67 publications

Signalling cross-talk between hepatocyte nuclear factor 4α and growth-hormone-activated STAT5b

Signalling cross-talk between hepatocyte nuclear factor 4α and growth-hormone-activated STAT5b

Sex Differences in Drug Metabolism

G‐protein‐coupled bile acid receptor plays a key role in bile acid metabolism and fasting‐induced hepatic steatosis in mice

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