Reduced ZMPSTE24 expression leads to prelamin accumulation and development of steatosis in MAFLD patients [RNA-seq]

Mutations of nuclear lamina-associated proteins LMNA and ZMPSTE24 have been associated with fatty liver. We report that the changes at the nuclear envelope we described in MAFLD patients are caused by downregulation of ZMPSTE24, an enzyme that processes prelamin to mature lamin A. In addition, Zmpste24 mutant mice develop hepatic steatosis and exhibit upregulation of p53 target genes. p53 activity is also induced in genes differentially expressed in MAFLD patients. Furthermore, p53 regulates genes bound by FOXA2 in these individuals, corresponding to observations in Zmpste24 mutants. In contrast, expression of glucose and insulin regulated genes is reduced in MAFLD patients, suggesting altered glucose metabolism and insulin resistance, hallmarks of type 2 diabetes (T2D). Hence, our genomics data show that MAFLD patients with severe steatosis but yet without MASH are already suffering from severe metabolic consequences and underscore the need for treatment at this stage of the disease. Overall design: Differential gene expression profiling analysis of RNA-seq data for liver tissues of 9 samples from female patients (3 control, 3 mild MAFLD, 3 moderate MAFLD) and 9 samples from male patients (3 control, 3 mild/moderate MAFLD, 3 severe MAFLD). Female donors were 17–59yr old (healthy, 17–59; MAFLD, 31–47) Male donors were 21–51yr old (healthy, 26–45; MAFLD, 21–51).

核纤层相关蛋白LMNA与ZMPSTE24的突变已被证实与脂肪肝存在关联。本研究发现，我们在代谢相关脂肪性肝病（MAFLD）患者中观测到的核膜改变，是由ZMPSTE24的表达下调所介导的——该酶负责将前层粘连蛋白加工为成熟层粘连蛋白A。此外，Zmpste24突变小鼠可出现肝脂肪变性，并表现出p53靶基因的表达上调。在MAFLD患者的差异表达基因中，p53的活性同样被激活。进一步研究显示，p53可调控此类受试者中被FOXA2结合的基因，这一结果与Zmpste24突变小鼠中的观测发现一致。与之相反，MAFLD患者体内葡萄糖与胰岛素调控基因的表达水平显著下调，提示其存在葡萄糖代谢紊乱与胰岛素抵抗——二者均为2型糖尿病（T2D）的典型病理特征。综上，本研究的基因组学数据表明，仅存在重度肝脂肪变性但未进展为代谢相关脂肪性肝炎（MASH）的MAFLD患者，已出现严重的代谢异常，这凸显了在疾病该阶段开展干预治疗的必要性。
实验整体设计：针对女性患者肝组织的9份RNA-seq样本开展差异基因表达谱分析（其中健康对照3份、轻度MAFLD患者3份、中度MAFLD患者3份），同时针对男性患者肝组织的9份RNA-seq样本开展相同分析（其中健康对照3份、轻中度MAFLD患者3份、重度MAFLD患者3份）。女性受试者年龄为17~59岁（健康人群：17~59岁；MAFLD患者：31~47岁）；男性受试者年龄为21~51岁（健康人群：26~45岁；MAFLD患者：21~51岁）。