title: Lipid profiling and transcriptomic analysis reveals a functional interplay between estradiol and growth hormone in liver.
abstract: 17β-estradiol (E2) may interfere with endocrine, metabolic, and gender-differentiated functions in liver in both females and males. Indirect mechanisms play a crucial role because of the E2 influence on the pituitary GH secretion and the GHR-JAK2-STAT5 signaling pathway in the target tissues. E2, through its interaction with the estrogen receptor, exerts direct effects on liver. Hypothyroidism also affects endocrine and metabolic functions of the liver, rendering a metabolic phenotype with features that mimic deficiencies in E2 or GH. In this work, we combined the lipid and transcriptomic analysis to obtain comprehensive information on the molecular mechanisms of E2 effects, alone and in combination with GH, to regulate liver functions in males. We used the adult hypothyroid-orchidectomized rat model to minimize the influence of internal hormones on E2 treatment and to explore its role in male-differentiated functions. E2 influenced genes involved in metabolism of lipids and endo-xenobiotics, and the GH-regulated endocrine, metabolic, immune, and male-specific responses. E2 induced a female-pattern of gene expression and inhibited GH-regulated STAT5b targeted genes. E2 did not prevent the inhibitory effects of GH on urea and amino acid metabolism-related genes. The combination of E2 and GH decreased transcriptional immune responses. E2 decreased the hepatic content of saturated fatty acids and induced a transcriptional program that seems to be mediated by the activation of PPARα. In contrast, GH inhibited fatty acid oxidation. Both E2 and GH replacements reduced hepatic CHO levels and increased the formation of cholesterol esters and triacylglycerols. Notably, the hepatic lipid profiles were endowed with singular fingerprints that may be used to segregate the effects of different hormonal replacements. In summary, we provide in vivo evidence that E2 has a significant impact on lipid content and transcriptome in male liver and that E2 exerts a marked influence on GH physiology, with implications in human therapy.
authors.affiliation: Department of Clinical Sciences, University of Las Palmas de Gran Canaria - Biomedical and Health Research Institute (IUIBS), Molecular and Translational Endocrinology Group, Las Palmas de Gran Canaria, Spain; Cancer Research Institute of The Canary Islands (ICIC), Las Palmas de Gran Canaria, Canary Islands, Spain.
authors.forename: Leandro
authors.initials: L
authors.lastname: Fernández-Pérez
authors.affiliation: Department of Clinical Sciences, University of Las Palmas de Gran Canaria - Biomedical and Health Research Institute (IUIBS), Molecular and Translational Endocrinology Group, Las Palmas de Gran Canaria, Spain.
authors.forename: Ruymán
authors.initials: R
authors.lastname: Santana-Farré
authors.affiliation: Department of Clinical Sciences, University of Las Palmas de Gran Canaria - Biomedical and Health Research Institute (IUIBS), Molecular and Translational Endocrinology Group, Las Palmas de Gran Canaria, Spain.
authors.forename: Mercedes
authors.initials: M
authors.lastname: de Mirecki-Garrido
authors.affiliation: Cancer Research Institute of The Canary Islands (ICIC), Las Palmas de Gran Canaria, Canary Islands, Spain; Department of Animal Biology, University of La Laguna, Laboratory of Membrane Physiology and Biophysics, La Laguna, Spain.
authors.forename: Irma
authors.initials: I
authors.lastname: García
authors.affiliation: Department of Clinical Sciences, University of Las Palmas de Gran Canaria - Biomedical and Health Research Institute (IUIBS), Molecular and Translational Endocrinology Group, Las Palmas de Gran Canaria, Spain; Cancer Research Institute of The Canary Islands (ICIC), Las Palmas de Gran Canaria, Canary Islands, Spain.
authors.forename: Borja
authors.initials: B
authors.lastname: Guerra
authors.affiliation: Department of Clinical Sciences, University of Las Palmas de Gran Canaria - Biomedical and Health Research Institute (IUIBS), Molecular and Translational Endocrinology Group, Las Palmas de Gran Canaria, Spain; Cancer Research Institute of The Canary Islands (ICIC), Las Palmas de Gran Canaria, Canary Islands, Spain.
authors.forename: Carlos
authors.initials: C
authors.lastname: Mateo-Díaz
authors.affiliation: Molecular Endocrinology group, University of Copenhagen - Novo Nordisk Center for Protein Research, Copenhagen, Denmark.
authors.forename: Diego
authors.initials: D
authors.lastname: Iglesias-Gato
authors.affiliation: Department of Clinical Sciences, University of Las Palmas de Gran Canaria - Biomedical and Health Research Institute (IUIBS), Molecular and Translational Endocrinology Group, Las Palmas de Gran Canaria, Spain; Cancer Research Institute of The Canary Islands (ICIC), Las Palmas de Gran Canaria, Canary Islands, Spain.
authors.forename: Juan Carlos
authors.initials: JC
authors.lastname: Díaz-Chico
authors.affiliation: Molecular Endocrinology group, University of Copenhagen - Novo Nordisk Center for Protein Research, Copenhagen, Denmark.
authors.forename: Amilcar
authors.initials: A
authors.lastname: Flores-Morales
authors.affiliation: Cancer Research Institute of The Canary Islands (ICIC), Las Palmas de Gran Canaria, Canary Islands, Spain; Department of Animal Biology, University of La Laguna, Laboratory of Membrane Physiology and Biophysics, La Laguna, Spain.
authors.forename: Mario
authors.initials: M
authors.lastname: Díaz
mesh_terms: D000818:Animals; D004958:Estradiol / Q000494:pharmacology*; D004967:Estrogens / Q000494:pharmacology; D005227:Fatty Acids / Q000032:analysis; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000187:drug effects; D053263:Gene Regulatory Networks / Q000187:drug effects; D013006:Growth Hormone / Q000494:pharmacology*; D007037:Hypothyroidism / Q000235:genetics; D050356:Lipid Metabolism / Q000235:genetics*; D008055:Lipids / Q000032:analysis / Q000097:blood; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D008957:Models, Genetic; D020411:Oligonucleotide Array Sequence Analysis; D009919:Orchiectomy; D017207:Rats, Sprague-Dawley; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D059467:Transcriptome / Q000235:genetics*
chemical_list: D004967:Estrogens; D005227:Fatty Acids; D008055:Lipids; D004958:Estradiol; D013006:Growth Hormone