Characterizing zonated hepatocyte sexual dimorphism and its role in fatty liver disease

性别是许多人类疾病的易感性和严重性的重要决定因素。然而 它作为一种生物学变量常常被忽视。肝脏是一个两性异形器官，这导致 男性和女性之间的肝脏疾病结果存在显着差异。其中包括非- 酒精性脂肪肝，影响超过25%的人口。目前，主要 我们对肝脏中性别差异的理解存在差距， 这些差异，以及性别差异对肝病转归的表现。 除了性别差异，肝脏也有明显的功能差异 沿着肝小叶，肝的基本功能单位。包括NAFLD在内的肝脏疾病也 在病理学上表现为沿着小叶的带状分布。到目前为止，人们对性行为是否 肝脏中的二态性沿肝小叶沿着均匀分布。 我们发现，超过一半的性二态肝细胞基因表现出空间多态性， 肝小叶的带状分布。令人惊讶的是，这些分区的性二态基因 在性别和小叶中不对称分布，这对应于带状性别 肝功能的差异。我们发现，驱动性别差异的系统信号表现出 明显的带状活动，而驱动带状活动的局部信号显示出明显的性二态性 活动最后，我们在一个肝损伤模型中显示了分区损伤和性别 肝细胞中的带状性二型性驱动性别的结果差异 肝脏对损伤反应的差异。 我们的假设是肝细胞的小叶带状和性二型性是 通过局部小叶信号（包括Wnt和 包括生长激素在内的全身信号。我们提出了一系列研究，以1）确定 局部和系统信号在建立分带性二型中的各自作用 肝细胞; 2）表征肝细胞中带状性二型性如何在不同的 青春期前、性成熟和更年期的不同生殖阶段;以及3） 描述不同生殖阶段肝脏对NAFLD反应的性别差异。 这些研究的结果将提高我们对性别差异如何影响肝脏的理解 疾病易感性和进展。

Sex is a strong determinant of susceptibility and severity for many human diseases. Yet it is often ignored as a biological variable. The liver is a sexually dimorphic organ, which leads to significant differences liver disease outcomes between men and women. This includes non- alcoholic fatty liver disease, which affects over 25% of the population. There are currently major gaps in our understanding of what the sex differences are in the liver, the mechanism that drive these differences, and the manifestations of sex differences on liver disease outcome. Besides sex differences, the liver is also known to have significant functional differences along the liver lobule, the basic functional unit of the liver. Liver diseases including NAFLD also show zonation along the lobule in their pathology. To date, little is known about whether sexual dimorphism in the liver is evenly distributed along the liver lobule. We showed that more than half of sexually dimorphic hepatocyte genes show spatial zonation across the liver lobule. Surprisingly these zonated sexual dimorphic genes are asymmetrically distributed across sex and the lobule, which corresponds to zonated sex differences in liver function. We showed that systemic signals that drive sex differences exhibit clear zonated activity while local signals that drive zonation show clear sexually dimorphic activity. Finally, we showed in a liver injury model that shows both zonated damage and sex differences in outcomes that zonated sexual dimorphism in hepatocytes drives the sex differences in the liver’s response to injury. Our hypothesis is that lobular zonation and sexual dimorphism in hepatocytes are coordinately regulated by the interactions between local lobular signals including Wnts and systemic signals including growth hormone. We propose a set of studies to 1) determine the respective roles of local and systemic signals in establishing zonated sexual dimorphism in hepatocytes; 2) characterize how zonated sexual dimorphism in hepatocytes change across different reproductive stages of prepuberty, sexual maturity and menopause; and 3) characterize sex differences in liver response to NAFLD across different reproductive stages. The results of these studies will improve our understanding of how sex differences affect liver disease susceptibility and progression.