Centre for Functional Genomics and Bio-Chips, Institute of Biochemistry, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia.
Medical Experimental Centre, Institute of Pathology, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia.
Sci Rep. 2017 Jan 18;7:40775. doi: 10.1038/srep40775.
Development of mice with hepatocyte knockout of lanosterol 14α-demethylase (H) from cholesterol synthesis is characterized by the progressive onset of liver injury with ductular reaction and fibrosis. These changes begin during puberty and are generally more aggravated in the knockout females. However, a subgroup of (pre)pubertal knockout mice (runts) exhibits a pronounced male prevalent liver dysfunction characterized by downregulated amino acid metabolism and elevated Casp12. RORC transcriptional activity is diminished in livers of all runt mice, in correlation with the depletion of potential RORC ligands subsequent to CYP51 disruption. Further evidence for this comes from the global analysis that identified a crucial overlap between hepatic Cyp51 and Rorc expression profiles. Additionally, the reduction in RORA and RORC transcriptional activity was greater in adult H females than males, which correlates well with their downregulated amino and fatty acid metabolism. Overall, we identify a global and sex-dependent transcriptional de-regulation due to the block in cholesterol synthesis during development of the Cyp51 knockout mice and provide in vivo evidence that sterol intermediates downstream of lanosterol may regulate the hepatic RORC activity.
从胆固醇合成中敲除角鲨烯 14α-脱甲基酶（H）的小鼠的发育特征为进行性肝损伤，伴有胆管反应和纤维化。这些变化始于青春期，在敲除雌性中通常更为严重。然而，亚组（青春期前）敲除小鼠（矮子）表现出明显的男性为主的肝功能障碍，其特征为氨基酸代谢下调和 Casp12 升高。在所有 runt 小鼠的肝脏中，RORC 转录活性均降低，与 CYP51 破坏后潜在的 RORC 配体耗竭相关。来自全球分析的进一步证据表明，肝 Cyp51 和 Rorc 表达谱之间存在关键重叠。此外，成年 H 雌性的 RORA 和 RORC 转录活性降低幅度大于雄性，这与它们下调的氨基酸和脂肪酸代谢非常吻合。总体而言，我们确定了由于胆固醇合成过程中的 Cyp51 敲除导致的全局和性别依赖性转录失调，并提供了体内证据，表明角鲨烯下游的固醇中间体可能调节肝 RORC 活性。
