Discovery of therapeutic agents targeting PKLR for NAFLD using drug repositioning
Journal article, 2022
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.
NAFLD
Systems biology
Circadian rhythms
Drug repositioning
PKLR
Author
Cheng Zhang
Royal Institute of Technology (KTH)
Zhengzhou University
Mengnan Shi
Royal Institute of Technology (KTH)
Woonghee Kim
Royal Institute of Technology (KTH)
Muhammad Arif
Royal Institute of Technology (KTH)
M. Klevstig
Sahlgrenska University Hospital
Xiangyu Li
Royal Institute of Technology (KTH)
Hong Yang
Royal Institute of Technology (KTH)
Cemil Bayram
Atatürk University
Ismail Bolat
Atatürk University
Özlem Özdemir Tozlu
Erzurum Technical University
Ahmet Hacımuftuoglu
Atatürk University
Serkan Yıldırım
Atatürk University
Jihad Sebhaoui
Biota Research & Development Center
Shazia Iqbal
Biota Research & Development Center
Yongjun Wei
Zhengzhou University
Xiaojing Shi
Zhengzhou University
Jens B Nielsen
Chalmers, Biology and Biological Engineering, Systems and Synthetic Biology
Hasan Turkez
Atatürk University
Mathias Uhlen
Royal Institute of Technology (KTH)
Jan Borén
Sahlgrenska University Hospital
Adil Mardinoglu
Royal Institute of Technology (KTH)
King's College London
EBioMedicine
2352-3964 (eISSN)
Vol. 83 104214Subject Categories
Pharmaceutical Sciences
Pharmacology and Toxicology
Medicinal Chemistry
DOI
10.1016/j.ebiom.2022.104214
PubMed
35988463