Department of Integrative Biology and Physiology, University of California, Los Angeles, Los Angeles, CA, USA.
Department of Medicine/Division of Cardiology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA.
Biol Sex Differ. 2018 Oct 22;9(1):46. doi: 10.1186/s13293-018-0205-7.
Non-alcoholic fatty liver disease (NAFLD) encompasses benign steatosis and more severe conditions such as non-alcoholic steatohepatitis (NASH), cirrhosis, and liver cancer. This chronic liver disease has a poorly understood etiology and demonstrates sexual dimorphisms. We aim to examine the molecular mechanisms underlying sexual dimorphisms in NAFLD pathogenesis through a comprehensive multi-omics study. We integrated genomics (DNA variations), transcriptomics of liver and adipose tissue, and phenotypic data of NAFLD derived from female mice of ~ 100 strains included in the hybrid mouse diversity panel (HMDP) and compared the NAFLD molecular pathways and gene networks between sexes.
We identified both shared and sex-specific biological processes for NAFLD. Adaptive immunity, branched chain amino acid metabolism, oxidative phosphorylation, and cell cycle/apoptosis were shared between sexes. Among the sex-specific pathways were vitamins and cofactors metabolism and ion channel transport for females, and phospholipid, lysophospholipid, and phosphatidylinositol metabolism and insulin signaling for males. Additionally, numerous lipid and insulin-related pathways and inflammatory processes in the adipose and liver tissue appeared to show more prominent association with NAFLD in male HMDP. Using data-driven network modeling, we identified plausible sex-specific and tissue-specific regulatory genes as well as those that are shared between sexes. These key regulators orchestrate the NAFLD pathways in a sex- and tissue-specific manner. Gonadectomy experiments support that sex hormones may partially underlie the sexually dimorphic genes and pathways involved in NAFLD.
Our multi-omics integrative study reveals sex- and tissue-specific genes, processes, and networks underlying sexual dimorphism in NAFLD and may facilitate sex-specific precision medicine.
非酒精性脂肪性肝病（NAFLD）包括良性脂肪变性和更严重的疾病，如非酒精性脂肪性肝炎（NASH）、肝硬化和肝癌。这种慢性肝病的病因尚不清楚，并表现出性别二态性。我们旨在通过全面的多组学研究来研究 NAFLD 发病机制中性别二态性的分子机制。我们整合了基因组学（DNA 变异）、肝脏和脂肪组织的转录组学以及来自杂交小鼠多样性面板（HMDP）中包含的约 100 个品系的雌性小鼠的 NAFLD 表型数据，并比较了性别之间的 NAFLD 分子途径和基因网络。
我们确定了 NAFLD 的共同和性别特异性生物学过程。适应性免疫、支链氨基酸代谢、氧化磷酸化和细胞周期/凋亡在两性之间是共同的。在性别特异性途径中，女性为维生素和辅因子代谢和离子通道转运，男性为磷脂、溶血磷脂和磷酸肌醇代谢和胰岛素信号。此外，脂肪和肝脏组织中的许多脂质和胰岛素相关途径和炎症过程似乎与雄性 HMDP 中的 NAFLD 更相关。使用数据驱动的网络建模，我们确定了可能的性别特异性和组织特异性调节基因以及两性共有的基因。这些关键调节因子以性别和组织特异性的方式协调 NAFLD 途径。性腺切除术实验支持性激素可能部分解释了 NAFLD 中涉及性别二态性的基因和途径。
我们的多组学综合研究揭示了 NAFLD 性别二态性的性别特异性和组织特异性基因、过程和网络，并可能促进性别特异性精准医学。
