Kim Ju-Yeon, Yang In Sook, Kim Hyeon-Ji, Yoon Jae-Yeun, Han Yong-Hyun, Seong Je Kyung, Lee Mi-Ock
College of Pharmacy, Seoul National University, Seoul, South Korea.
College of Veterinary Medicine, Seoul National University, Seoul, South Korea.
Am J Physiol Endocrinol Metab. 2022 Feb 1;322(2):E118-E131. doi: 10.1152/ajpendo.00309.2021. Epub 2021 Dec 13.
Hepatic polyploidization is closely linked to the progression of nonalcoholic fatty liver disease (NAFLD); however, the underlying molecular mechanism is not clearly understood. In this study, we demonstrated the role of retinoic acid-related orphan receptor α (RORα) in the maintenance of genomic integrity, particularly in the pathogenesis of NAFLD, using the high-fat diet (HFD)-fed liver-specific RORα knockout (RORα-LKO) mouse model. First, we observed that the loss of hepatic retinoic acid receptor-related orphan receptor α (RORα) accelerated hepatocyte nuclear polyploidization after HFD feeding. In 70% partial hepatectomy experiments, enrichment of hepatocyte polyploidy was more obvious in the RORα-LKO animals, which was accompanied by early progression to the S phase and blockade of the G2/M transition, suggesting a potential role of RORα in suppressing hepatocyte polyploidization in the regenerating liver. An analysis of a publicly available RNA sequencing (RNA-seq) and chromatin immunoprecipitation-seq dataset, together with the Search Tool of the Retrieval of Interacting Genes/Proteins database resource, revealed that DNA endoreplication was the top-enriched biological process Gene Ontology term. Furthermore, we found that and , which encode key transcription factors for DNA endoreplication, were the downstream targets of RORα-induced transcriptional repression. Finally, we showed that the administration of JC1-40, an RORα activator (5 mg/kg body wt), significantly reduced hepatic nuclear polyploidization in the HFD-fed mice. Together, our observations suggest that the RORα-induced suppression of hepatic polyploidization may provide new insights into the pathological polyploidy of NAFLD and may contribute to the development of therapeutic strategies for the treatment of NAFLD. It has been reported that hepatic polyploidization is closely linked to the progression of NAFLD. Here, we showed that the genetic depletion of hepatic RORα in mice accelerated hepatocyte polyploidization after high-fat diet feeding. The mechanism could be the RORα-mediated repression of and , key transcription factors for DNA endoreplication. Thus, preservation of genome integrity by RORα could provide a new insight for developing therapeutics against the disease.
肝多倍体化与非酒精性脂肪性肝病（NAFLD）的进展密切相关；然而，其潜在的分子机制尚不清楚。在本研究中，我们使用高脂饮食（HFD）喂养的肝脏特异性视黄酸相关孤儿受体α（RORα）基因敲除（RORα-LKO）小鼠模型，证明了视黄酸相关孤儿受体α（RORα）在维持基因组完整性中的作用，特别是在NAFLD的发病机制中的作用。首先，我们观察到肝脏视黄酸受体相关孤儿受体α（RORα）的缺失加速了HFD喂养后肝细胞的核多倍体化。在70%部分肝切除实验中，RORα-LKO动物中肝细胞多倍体的富集更为明显，这伴随着早期进入S期和G2/M期转换的阻滞，提示RORα在抑制再生肝脏中肝细胞多倍体化方面具有潜在作用。对公开可用的RNA测序（RNA-seq）和染色质免疫沉淀测序数据集的分析，以及对相互作用基因/蛋白质数据库资源检索工具的分析，揭示DNA核内复制是富集程度最高的生物学过程基因本体术语。此外，我们发现编码DNA核内复制关键转录因子的 和 是RORα诱导的转录抑制的下游靶点。最后，我们表明给予RORα激活剂JC1-40（5mg/kg体重）可显著降低HFD喂养小鼠的肝细胞核多倍体化。总之，我们的观察结果表明，RORα诱导的肝多倍体化抑制可能为NAFLD的病理性多倍体提供新的见解，并可能有助于开发NAFLD的治疗策略。据报道，肝多倍体化与NAFLD的进展密切相关。在这里，我们表明小鼠肝脏RORα的基因缺失加速了高脂饮食喂养后肝细胞的多倍体化。其机制可能是RORα介导的对DNA核内复制关键转录因子 和 的抑制。因此，RORα对基因组完整性的保护可为开发针对该疾病的治疗方法提供新的见解。
