[review] sex dimorphism in nuclear receptor signaling

Men and women have different organs, including the liver. The reasons for this sex difference are not completely clear, but probably relies on some different metabolic needs occurring during the reproduction. This is particularly evident in lay-egg animals like fishes and birds: to make egg nutrients, the liver is stimulated by the estrogen hormone to increase lipid and protein production (vitellogenesis). In mammals also (and humans, ditto) hormones like estrogen, and other nutrients (i.e., dietary lipids), can activate liver gene expression by binding to cognate 'nuclear receptors' (NRs). In fact, nuclear receptors can modulate the transcriptional rates of genes involved in a broad range of metabolic response programs. Because i) liver gene expression is different between females and males, and ii) the liver metabolic landscape is sex dimorphic, one can argue NRs having some gender-dimorphic activities. However, in most studies only one sex is used (the male for some authors, the female for others), this introduces a bias in our knowledge and makes the sex differences pass unobserved.

Fat liver (steatosis or 'foie gras') is an hallmark of severe diseases including liver cancer. Derangements of nuclear receptor regulation affect lipid metabolism and contribute to the pathogenesis of liver diseases. This places nuclear receptors into the frontline for novel therapeutic approaches for a broad range of hepatic disorders. Detailing the extent of NR-mediated sex-dimorphic actions may be pivotal in preventive medicine and in the design of safer gender-specific therapeutic approaches.

Martin Wagner and colleagues, have recently reviewed the wide role of nuclear receptors in regulating liver metabolism. We complete this review with a second one focusing on the current knowledge of hepatic, sex-associated roles of individual NRs. We show that sexual dimorphism affects both the level of individual gene expression and the concerted activities of interconnected genes controlled by nuclear receptors. Finally, we discuss the hypothesis that this sex-dimorphic NR ‘interactome’ targets selected pathways in the liver, and deregulation of these pathways may favor the development of sex-biased diseases.

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Wagner, M., Zollner, G., & Trauner, M. (2011). Nuclear receptors in liver disease Hepatology DOI: 10.1002/hep.24148

Rando, G., & Wahli, W. (2011). Sex differences in nuclear receptor-regulated liver metabolic pathways Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease DOI: 10.1016/j.bbadis.2010.12.023