GSK621 ameliorates lipid accumulation via AMPK pathways and reduces oxidative stress in hepatocytes in vitro and in obese mice in vivo

Introduction

Metabolic-dysfunction-associated fatty liver disease (MAFLD) represents a broad spectrum of liver lipid metabolism disorders associated with metabolic homeostasis, inflammation, oxidative stress, and fibrogenesis. The incidence of MAFLD has increased in recent years, but there is a lack of effective treatment strategies. GSK621 shows potential as a novel adenosine-monophosphate-activated protein kinase (AMPK) agonist; however, its function in lipid metabolism has not yet been confirmed.

Objectives

This study aimed to determine the effects of GSK621 on liver lipid accumulation in vitro and vivo and explore the underlying mechanism of these effects.

Methods

The function of GSK621 in lipid deposition was investigated in vitro with HepG2 cells and normal mouse liver cells (AML12), and in vivo using C57BL/6 J mice fed with a high-fat diet (60 % fat) for 8 weeks to establish a model of MAFLD, followed by GSK621 treatment for a further 8 weeks.

Results

GSK621 treatment significantly improved hepatocyte steatosis via the AMPK–carnitine palmitoyl transferase 1 (CPT1A) pathway and decreased levels of reactive oxygen species (ROS) in cells, accompanied by elevated expression of antioxidative stress proteins. MAFLD mice showed significant improvements in liver steatosis after GSK621 treatment, as well as increased expression of liver proteins related to the AMPK pathway and antioxidative stress.

Conclusion

GSK621 can improve hepatocytes steatosis in vitro and vivo via the AMPK–CPT1A pathway by increasing lipid metabolism and augmenting expression of antioxidant-stress-related proteins to reduce ROS deposition.