Discovery of therapeutic agents targeting PKLR for NAFLD using drug repositioning
Artikel i vetenskaplig tidskrift, 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
Författare
Cheng Zhang
Kungliga Tekniska Högskolan (KTH)
Zhengzhou University
Mengnan Shi
Kungliga Tekniska Högskolan (KTH)
Woonghee Kim
Kungliga Tekniska Högskolan (KTH)
Muhammad Arif
Kungliga Tekniska Högskolan (KTH)
M. Klevstig
Sahlgrenska universitetssjukhuset
Xiangyu Li
Kungliga Tekniska Högskolan (KTH)
Hong Yang
Kungliga Tekniska Högskolan (KTH)
Cemil Bayram
Atatürk Üniversitesi
Ismail Bolat
Atatürk Üniversitesi
Özlem Özdemir Tozlu
Erzurum Teknik Üniversitesi
Ahmet Hacımuftuoglu
Atatürk Üniversitesi
Serkan Yıldırım
Atatürk Üniversitesi
Jihad Sebhaoui
Biota Research & Development Center
Shazia Iqbal
Biota Research & Development Center
Yongjun Wei
Zhengzhou University
Xiaojing Shi
Zhengzhou University
Jens B Nielsen
Chalmers, Biologi och bioteknik, Systembiologi
Hasan Turkez
Atatürk Üniversitesi
Mathias Uhlen
Kungliga Tekniska Högskolan (KTH)
Jan Borén
Sahlgrenska universitetssjukhuset
Adil Mardinoglu
Kungliga Tekniska Högskolan (KTH)
King's College London
EBioMedicine
2352-3964 (eISSN)
Vol. 83 104214Ämneskategorier
Farmaceutisk vetenskap
Farmakologi och toxikologi
Läkemedelskemi
DOI
10.1016/j.ebiom.2022.104214
PubMed
35988463