Department of Biomedical Sciences, Cornell University, Ithaca, New York 14853.
Center for Animal Resources and Education, Cornell University, Ithaca, New York 14853.
J Biol Chem. 2019 Oct 25;294(43):15623-15637. doi: 10.1074/jbc.RA118.005729. Epub 2019 Aug 21.
Defects in the Fanconi anemia (FA) DNA damage-response pathway result in genomic instability, developmental defects, hematopoietic failure, cancer predisposition, and metabolic disorders. The endogenous sources of damage contributing to FA phenotypes and the links between FA and metabolic disease remain poorly understood. Here, using mice lacking the gene, encoding a central FA pathway component, we investigated whether the FA pathway protects against metabolic challenges. and wildtype (WT) mice were fed a standard diet (SD), a diet enriched in fat, cholesterol, and cholic acid (Paigen diet), or a diet enriched in lipid alone (high-fat diet (HFD)). mice developed hepatobiliary disease and exhibited decreased survival when fed a Paigen diet but not a HFD. Male Paigen diet-fed mice lacking had significant biliary hyperplasia, increased serum bile acid concentration, and increased hepatic pathology. In contrast, female mice were similarly impacted by Paigen diet feeding regardless of status. Upon Paigen diet challenge, male mice had altered expression of genes encoding hepatic bile acid transporters and cholesterol and fatty acid metabolism proteins, including , , , , , and Untargeted lipidomic profiling in liver tissue revealed 132 lipid species, including sphingolipids, glycerophospholipids, and glycerolipids, that differed significantly in abundance depending on status in male mice. We conclude that the FA pathway has sex-specific impacts on hepatic lipid and bile acid metabolism, findings that expand the known functions of the FA pathway and may provide mechanistic insight into the metabolic disease predisposition in individuals with FA.
范可尼贫血（FA）的 DNA 损伤反应途径缺陷导致基因组不稳定性、发育缺陷、造血衰竭、癌症易感性和代谢紊乱。导致 FA 表型的内源性损伤源以及 FA 和代谢疾病之间的联系仍知之甚少。在这里，我们使用缺乏编码 FA 通路核心成分的 基因的小鼠，研究了 FA 通路是否能抵抗代谢挑战。 和野生型（WT）小鼠分别喂食标准饮食（SD）、富含脂肪、胆固醇和胆酸的饮食（Paigen 饮食）或仅富含脂质的饮食（高脂肪饮食（HFD））。 缺乏 基因的小鼠在喂食 Paigen 饮食时会发生肝胆疾病并表现出存活率降低，但喂食 HFD 时则不会。缺乏 基因的雄性 Paigen 饮食喂养的小鼠出现显著的胆管增生、血清胆汁酸浓度增加和肝病理改变。相比之下，无论 状态如何，雌性小鼠同样受到 Paigen 饮食喂养的影响。在 Paigen 饮食挑战下，雄性 缺乏 基因的小鼠肝脏中编码胆汁酸转运体和胆固醇及脂肪酸代谢蛋白的基因表达发生改变，包括 、 、 、 、 和 。在肝组织中进行的非靶向脂质组学分析揭示了 132 种脂质种类，包括鞘脂、甘油磷脂和甘油三酯，它们的丰度根据雄性小鼠中 基因的状态而显著不同。我们得出结论，FA 途径对肝脏脂质和胆汁酸代谢具有性别特异性影响，这些发现扩展了 FA 途径的已知功能，并可能为 FA 个体代谢疾病易感性提供机制见解。
