Wauthier Valerie, Sugathan Aarathi, Meyer Rosana D, Dombkowski Alan A, Waxman David J
Division of Cell and Molecular Biology, Department of Biology, Boston University, Boston, Massachusetts 02215, USA.
Mol Endocrinol. 2010 Mar;24(3):667-78. doi: 10.1210/me.2009-0454. Epub 2010 Feb 11.
Sex differences in liver gene expression are dictated by sex differences in circulating GH profiles. Presently, the pituitary hormone dependence of mouse liver gene expression was investigated on a global scale to discover sex-specific early GH response genes that could contribute to sex-specific regulation of downstream GH targets and to ascertain whether intrinsic sex differences characterize hepatic responses to plasma GH stimulation. Global RNA expression analysis identified two distinct classes of sex-specific mouse liver genes: genes subject to positive regulation (class I) and genes subject to negative regulation by pituitary hormones (class II). Genes activated or repressed in hypophysectomized (Hypox) mouse liver within 30-90 min of GH pulse treatment at a physiological dose were identified as putative direct targets of GH action (early response genes). Intrinsic sex differences in the GH responsiveness of a subset of these early response genes were observed. Notably, 45 male-specific genes, including five encoding transcriptional regulators that may mediate downstream sex-specific transcriptional responses, were induced by GH within 30 min in Hypox male but not Hypox female mouse liver. The early GH response genes were enriched in 29 male-specific targets of the transcription factor myocyte enhancer factor 2, whose activation in hepatic stellate cells is associated with liver fibrosis leading to hepatocellular carcinoma, a male-predominant disease. Thus, the rapid activation by GH pulses of certain sex-specific genes is modulated by intrinsic sex-specific factors, which may be associated with prior hormone exposure (epigenetic mechanisms) or genetic factors that are pituitary-independent, and could contribute to sex differences in predisposition to liver cancer or other hepatic patho-physiologies.
肝脏基因表达中的性别差异由循环生长激素（GH）谱的性别差异所决定。目前，在全球范围内研究了小鼠肝脏基因表达对垂体激素的依赖性，以发现可能有助于下游GH靶标性别特异性调节的性别特异性早期GH反应基因，并确定肝脏对血浆GH刺激的反应是否具有内在性别差异特征。全基因组RNA表达分析确定了两类不同的性别特异性小鼠肝脏基因：受正向调节的基因（I类）和受垂体激素负向调节的基因（II类）。在生理剂量的GH脉冲处理30 - 90分钟内，在垂体切除（Hypox）小鼠肝脏中被激活或抑制的基因被确定为GH作用的假定直接靶标（早期反应基因）。观察到这些早期反应基因的一个子集中GH反应性存在内在性别差异。值得注意的是，45个雄性特异性基因，包括5个编码可能介导下游性别特异性转录反应的转录调节因子，在Hypox雄性小鼠肝脏中30分钟内被GH诱导，而在Hypox雌性小鼠肝脏中未被诱导。早期GH反应基因在转录因子肌细胞增强因子2的29个雄性特异性靶标中富集，其在肝星状细胞中的激活与导致肝细胞癌（一种男性为主的疾病）的肝纤维化相关。因此，GH脉冲对某些性别特异性基因的快速激活受到内在性别特异性因素的调节，这些因素可能与先前的激素暴露（表观遗传机制）或与垂体无关的遗传因素有关，并可能导致肝癌或其他肝脏病理生理学易感性的性别差异。
