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.
Highlights
Estradiol inhibits the effects of growth hormone (GH) on somatotropic-liver axis and induces negative regulators of GH-STAT5 signaling and a female-pattern of gene expression in adult hypothyroid-orchidectomized rat liver Upon sacrifice on PND94, biochemical hypothyroidism was shown, and significantly (P = 0.001) lower or undetectable serum levels of T3 [36.1765.43 (INTACT); 7.9264.84 (TXOX); 1.4862.14 (TXOXE2); 0 (TXOXGH); 0.1460.33 (TXOXE2GH)] and T4 [(1.9060.17 (INTACT) vs. 0)] were found in all TXOX groups in comparison with the age-matched euthyroid control group (INTACT)
E2 treatment of TXOX rats induced the mRNA expression of SOCS2 (Fig. 1D) and CIS (Fig.1E), but only to a fraction of the levels obtained after GH treatment
Our microarray analysis showed that male predominant genes (e.g., CYP2C11, CYP2C13, CYP2E1, alpha-2u-globulin) were down-regulated by E2, whereas female predominant genes (e.g., CYP2C12, CYP2A1, CYP2C7) were induced [15]. These findings demonstrate that E2 influences the transcription of GHR-STAT5 targeted genes and induces a female-pattern of gene expression in TXOX rat liver
Summary
17b-estradiol (E2), a major natural estrogen in mammals, has physiological actions not limited to reproductive organs in males [1,2,3,4,5,6]. An insufficient E2 signaling in the ERKO and ArKO null mice models results in a metabolic syndrome-like phenotype with fatty liver due to a disruption in b-oxidation and increased lipogenesis, a phenotype that is reversed by physiological doses of E2. Both of these models exhibit a sexually dimorphic fatty liver that, notably, is male specific [1]. Animal studies of hepatic effects of E2 or its interplay with GH actions have been focused on females [24,25] It is unclear if males exhibit equivalent responses, and there are reasons why such equivalence should not be presumed. Hepatic lipid profiles from E2- and/or GH-treated TXOX rats substantially differ from those observed in intact animals, indicating that the normal functions of thyroid glands and testes are an absolute requirement for physiological hepatic lipid homeostasis
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