Control of Liver Gene Expression by Sex Steroids and Growth Hormone Interplay

Abstract

Sex steroids have important physiological actions, which are not limited to reproductive organs, in both females and males. They exert important physiological roles, including the regulation of somatotropic-liver axis, intermediate metabolism, or gender dimorphism. This is in part because the liver is a sex steroid-responsive organ where sex steroid-and growth hormone (GH)-dependent signaling pathways connect to regulate complex gene expression networks. Sex steroids can impact liver gene expression by a direct, through hepatic estrogen receptor (ER)α and androgen receptor (AR), or indirect mechanisms, by modulation of pituitary GH secretion and/or interaction with the GHR-STAT5b signaling pathway. Therefore, deficiency of sex steroid-and GH-dependent signaling pathways might cause a dramatic impact on mammalian liver physiology. In this chapter, we will focus our attention on main concepts and paradigms involved in the role and interplay between sex steroid-and GH-dependent signaling to regulate gene expression networks in the mammalian liver. A better understanding of how sex steroids and interactions with GH-STAT5b signaling pathway influence physiological and pathological states in the liver will contribute to improve clinical management of patients with disorders in body growth, development, and metabolism.Chemistry and Biological Activity of Steroids 2 androgen/AR [6,7,[21][22][23][24][25] or signaling pathways in adults causes a similar metabolic-like syndrome (i.e., fatty liver, adiposity, insulin resistance), a phenotype that might be ameliorated by E2/T or GH replacement. Therefore, the interplay between sex steroids and GH is clinically relevant because of its importance in the regulation of endocrine, metabolic, and gender-differentiated actions on the mammalian liver [33]. A better understanding of this complex sex steroid-GH interplay in physiological and pathological states will contribute to prevent health damage and improve clinical management of patients with growth, developmental, and metabolic disorders. In this review, we will summarize the role of sex steroid-and GH-dependent signaling pathways on liver gene expression. The liver is as sex steroid-responsive organSex steroids can regulate liver gene transcription through direct and indirect mechanisms.

Gene expression dynamics during rapid organismal diversification in African cichlid fishes

“…Sex-biased gene expression in liver has been reported before 4 , albeit with a smaller magnitude than observed here. These sex differences in liver gene expression can mainly be attributed to its function as the main metabolic organ secreting hormones and maintaining homeostasis, and being responsive to sex steroids 28 – 33 (for an in-depth analysis of sex-specific differences in Tanganyikan cichlid fishes as well as of sex chromosome evolution see ref. 34 ).…”

Hepatic sexual dimorphism — implications for non-alcoholic fatty liver disease

“…The mechanism through which GH determines hepatic sexual dimorphism is under intense investigation 53 . For instance, the level of expression of genes that regulate lipid, cholesterol and drug metabolism in the adult liver is determined by the GH secretion pattern 43 , which in rats is established by androgen exposure (which causes persistent epigenetic changes) during the neonatal period 54,55 .…”

Sex differences in non-alcoholic fatty liver disease: hints for future management of the disease

“…In male post-pubertal rats, the activation of the GHR-STAT5b pathway is episodic, with low levels of circulating GH are required to achieve maximal activation of STAT5b-mediated transcription. On the other hand, the GH secretion in female rats is continuous with a reduced STAT5b activation compared with males [96]. Aside from its role in lipid metabolism, emerging evidence also found that STAT5b has a crucial role in maintaining glucose homeostasis.…”