GSE193627
Discovery of therapeutic agents targeting PKLR for NAFLD using drug repositioning
Background & Aims  Non-alcoholic fatty liver disease (NAFLD) encompasses a wide spectrum of liver pathologies. However, not medical treatment has been approved for the disease so far. In our previous study, we found PKLR could be a potential target for treatment of NALFD. Here the aim is to investigate the effect of PKLR in in vivo model and reposition a drug which could be used for treatment of NAFLD.   Results  The Pklr KO reversed the increased hepatic triglyceride level in mice fed with high sucrose diet and partly recovered the transcriptomic changes in liver as well as 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 drugs were identified as potential inhibitor of PKLR by the 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 it was demonstrated that these drugs attenuated hepatic steatosis without side effect on other tissues.  Conclusion: 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 could be validated in further clinical trials. Overall design: Eight male C57BL/6J mice wild-type mice and eight Pklr-/- mutant mice were fed a standard mouse chow diet and housed in a 12-h light–dark cycle. From the age of 8 weeks, both the wild-type and mutant mice were then divided into two groups of 4 mice fed with chow diet, high-sucrose diet for another 8 weeks, respectively. At the age of 16 weeks, all mice are sacrificed and necropsies from liver, muscle, WAT and heart tissue were taken for RNA sequencing and lipid quantification.