Abstract
Background & Aims Non-alcoholic fatty liver disease (NAFLD) encompasses a wide spectrum of liver pathologies. However, not medical treatment has been approved for the treatment of the disease. 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 perform drug repositioning to identify a drug candidate for treatment of NAFLD.
Methods Biopsies from liver, muscle, white adipose tissue and heart were obtained from control and PKLR knockout mice fed with chow and high sucrose diets. Lipidomics as well as transcriptmics 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 finally tested in both in vitro and in vivo models to evaluated their toxicity and efficacy.
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 has been validated in preclinical experiment.
Competing Interest Statement
AM, JB and MU are the founder and shareholders of ScandiEdge Therapeutics and they filed a patent application on the use of small molecules to treat NAFLD patients. The other authors declare no competing interests
Footnotes
Conflict of interest statement: AM, JB and MU are the founder and shareholders of ScandiEdge Therapeutics and they filed a patent application on the use of small molecules to treat NAFLD patients. The other authors declare no competing interests.
Financial support statement: This work was financially supported by ScandiEdge Therapeutics and Knut and Alice Wallenberg Foundation.