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.

Hepatic polypeptide nutrient solution improves high‐cholesterol diet‐induced rats with nonalcoholic fatty liver disease by activating AMP‐activated protein kinase signaling pathway

“…Research indicates that increased hepatic lipogenesis in NAFLD patients is associated with activating SREBP‐1c, a transcription factor that plays a major role in regulating lipogenic proteins such as FAS. Overexpression of SREBP‐1c has been shown to induce hepatocyte steatosis, and AMPK is responsible for controlling SREBP‐1c activity in the liver (Fang et al., 2022 ; Kawamura et al., 2022 ; Liu et al., 2023 ). PPARα, a ligand activator, controls various aspects of lipid catabolism and serves as a major regulator of lipid oxidation in the liver, thus reducing hepatic lipid levels (Jia et al., 2013 ; Rakhshandehroo et al., 2010 ).…”

“…to induce hepatocyte steatosis, and AMPK is responsible for controlling SREBP-1c activity in the liver (Fang et al, 2022;Kawamura et al, 2022;Liu et al, 2023). PPARα, a ligand activator, controls various aspects of lipid catabolism and serves as a major regulator of lipid oxidation in the liver, thus reducing hepatic lipid levels (Jia et al, 2013;Rakhshandehroo et al, 2010).…”

Beneficial Effects of 6-Gingerol on Fatty Pancreas Disease in High-Fat High-Fructose Diet-Induced Metabolic Syndrome Rat Model

“…6,7 In addition, 6-G was reported to ameliorate hepatic steatosis by activating the LKB1/AMPK pathway. 8 6-Gingerol treatment also significantly reduced the levels of triglyceride, cholesterol, glucose, insulin resistance, and leptin while increasing the levels of liver antioxidant enzymes and adiponectin. 9,10 Although 6-G has been shown to have antioxidant and antiobesity properties in numerous studies, its potential to reduce lipid accumulation in pancreatic tissues has not been investigated.…”

“…Previous studies have proven that 6-gingerol (6-G), the active compound of ginger, has activity as an antioxidant, antiobesity, antidiabetic, antinausea, and antiemetic triggered by chemotherapy 6,7 . In addition, 6-G was reported to ameliorate hepatic steatosis by activating the LKB1/AMPK pathway 8 . 6-Gingerol treatment also significantly reduced the levels of triglyceride, cholesterol, glucose, insulin resistance, and leptin while increasing the levels of liver antioxidant enzymes and adiponectin 9,10 …”

Natural compounds proposed for the management of non-alcoholic fatty liver disease

“…6-Gingerol ( C4 ), an alkylated phenol from ginger, has various pharmacological effects, including a reduction of inflammatory factors and oxidative stress, an improvement of lipid profile and a reduction of glycemia [ 80 , 81 ]. Several recent studies have shown that the lipid-lowering and antidiabetic effects of 6-gingerol are mediated by PPAR receptors [ 82 , 83 ], notably the PPAR-γ receptor, allowing it to induce hypoglycemic and anti-hyperglycemic effects via a decrease in the expression of SREBP-1c and ChREBP [ 84 , 85 ].…”