利用药物重定位发现针对 PKLR 的治疗非酒精性脂肪性肝病的药物。

Discovery of therapeutic agents targeting PKLR for NAFLD using drug repositioning.

机构信息

Science for Life Laboratory, KTH - Royal Institute of Technology, Stockholm, Sweden; School of Pharmaceutical Sciences & Key Laboratory of Advanced Drug Preparation Technologies, Ministry of Education, Zhengzhou University, Zhengzhou, Henan Province, 450001, PR China.

Science for Life Laboratory, KTH - Royal Institute of Technology, Stockholm, Sweden.

出版信息

EBioMedicine. 2022 Sep;83:104214. doi: 10.1016/j.ebiom.2022.104214. Epub 2022 Aug 18.

DOI:10.1016/j.ebiom.2022.104214

PMID:35988463

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC9420484/

Abstract

BACKGROUND

Non-alcoholic fatty liver disease (NAFLD) encompasses a wide spectrum of liver pathologies. However, no medical treatment has been approved for the treatment of NAFLD. In our previous study, we found that PKLR could be a potential target for treatment of NALFD. Here, we investigated the effect of PKLR in in vivo model and performed drug repositioning to identify a drug candidate for treatment of NAFLD.

METHODS

Tissue samples from liver, muscle, white adipose and heart were obtained from control and PKLR knockout mice fed with chow and high sucrose diets. Lipidomics as well as transcriptomics analyses were conducted using these tissue samples. In addition, a computational drug repositioning analysis was performed and drug candidates were identified. The drug candidates were both tested in in vitro and in vivo models to evaluate their toxicity and efficacy.

FINDINGS

The Pklr KO reversed the increased hepatic triglyceride level in mice fed with high sucrose diet and partly recovered the transcriptomic changes in the liver as well as in other three tissues. Both liver and white adipose tissues exhibited dysregulated circadian transcriptomic profiles, and these dysregulations were reversed by hepatic knockout of Pklr. In addition, 10 small molecule drug candidates were identified as potential inhibitor of PKLR using our drug repositioning pipeline, and two of them significantly inhibited both the PKLR expression and triglyceride level in in vitro model. Finally, the two selected small molecule drugs were evaluated in in vivo rat models and we found that these drugs attenuate the hepatic steatosis without side effect on other tissues.

INTERPRETATION

In conclusion, our study provided biological insights about the critical role of PKLR in NAFLD progression and proposed a treatment strategy for NAFLD patients, which has been validated in preclinical studies.

FUNDING

ScandiEdge Therapeutics and Knut and Alice Wallenberg Foundation.

摘要

背景

非酒精性脂肪性肝病（NAFLD）涵盖了广泛的肝脏病理学。然而，目前还没有批准用于治疗 NAFLD 的医疗方法。在我们之前的研究中，我们发现 PKLR 可能是治疗 NALFD 的潜在靶点。在这里，我们研究了 PKLR 在体内模型中的作用，并进行了药物再定位，以确定治疗 NAFLD 的候选药物。

方法

从给予标准饮食和高蔗糖饮食的 PKLR 敲除和野生型小鼠的肝脏、肌肉、白色脂肪和心脏组织中获取组织样本。使用这些组织样本进行脂质组学和转录组学分析。此外，还进行了计算药物再定位分析，并确定了候选药物。在体外和体内模型中测试候选药物，以评估其毒性和疗效。

结果

Pklr KO 逆转了高蔗糖饮食喂养的小鼠肝脏甘油三酯水平升高，并部分恢复了肝脏以及其他三种组织的转录组变化。肝脏和白色脂肪组织都表现出昼夜节律转录组谱失调，而这种失调在 Pklr 肝敲除后得到了逆转。此外，使用我们的药物再定位管道，鉴定了 10 种小分子药物候选物作为 PKLR 的潜在抑制剂，其中两种在体外模型中显著抑制了 PKLR 的表达和甘油三酯水平。最后，在体内大鼠模型中评估了这两种选定的小分子药物，我们发现这些药物可减轻肝脂肪变性，而对其他组织无副作用。