6-Gingerol Ameliorates Hepatic Steatosis, Inflammation and Oxidative Stress in High-Fat Diet-Fed Mice through Activating LKB1/AMPK Signaling.

Abstract

6-Gingerol, one of the major pharmacologically active ingredients extracted from ginger, has been reported experimentally to exert hepatic protection in non-alcoholic fatty liver disease (NAFLD). However, the molecular mechanism remains largely elusive. RNA sequencing indicated the significant involvement of the AMPK signaling pathway in 6-gingerol-induced alleviation of NAFLD in vivo. Given the significance of the LKB1/AMPK pathway in metabolic homeostasis, this study aims to investigate its role in 6-gingerol-induced mitigation on NAFLD. Our study showed that 6-gingerol ameliorated hepatic steatosis, inflammation and oxidative stress in vivo and in vitro. Further experiment validation suggested that 6-gingerol activated an LKB1/AMPK pathway cascade in vivo and in vitro. Co-immunoprecipitation analysis demonstrated that the 6-gingerol-elicited activation of an LKB1/AMPK pathway cascade was related to the enhanced stability of the LKB1/STRAD/MO25 complex. Furthermore, radicicol, an LKB1 destabilizer, inhibited the activating effect of 6-gingerol on an LKB1/AMPK pathway cascade via destabilizing LKB1/STRAD/MO25 complex stability in vitro, thus reversing the 6-gingerol-elicited ameliorative effect. In addition, molecular docking analysis further predicated the binding pockets of LKB1 necessary for binding with 6-gingerol. In conclusion, our results indicate that 6-gingerol plays an important role in regulating the stability of the LKB1/STRAD/MO25 complex and the activation of LKB1, which might weigh heavily in the 6-gingerol alleviation of NAFLD.

• Authors: Yuzhe Liu, Dong Li, Shang Wang, Ze Peng, Qi Tan, Qifeng He, Jianwei Wang
• Journal: International journal of molecular sciences (Int J Mol Sci) Vol. 24 Issue 7 (Mar 27 2023) ISSN: 1422-0067 [Electronic] Switzerland
• PMID: 37047258 (Publication Type: Journal Article)

Chemical References

• AMP-Activated Protein Kinase Kinases
• AMP-Activated Protein Kinases
• gingerol
• Protein Serine-Threonine Kinases

Topics

• Animals
• Mice
• AMP-Activated Protein Kinase Kinases
• AMP-Activated Protein Kinases (metabolism)
• Diet, High-Fat
• Inflammation (drug therapy, metabolism)
• Liver (metabolism)
• Mice, Inbred C57BL
• Molecular Docking Simulation
• Non-alcoholic Fatty Liver Disease (drug therapy, etiology, metabolism)
• Oxidative Stress
• Protein Serine-Threonine Kinases (metabolism)