Abstract
Purpose: The objective of this study was to determine how metformin regulates the major activator of hepatic gluconeogenesis, peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α) and the PGC-1α controlled liver functions. Methods: In population study, we selected 40-69 years old patients with NAFLD, 77, and 102 healthy subjects as a control group. We detect the levels of serum PGC-1α, MDA and the activity of SOD of the two groups. In vitro study, L-02 cells were treated by 20 μg/ml oleic acid to induce the NAFLD cells model. The control group added ordinary 1640 culture medium. The model group cells were cultured in the medium containing 2.5, 5, 7.5mmol/l concentrations of metformin. Used RT-PCR analysis of PGC-1α mRNA, detected the level of triglycerides in cells, measured the content of MDA and the activity of SOD. Results: In population study, the level of MDA in the case group were increased obviously and the activity of SOD was decreased compared with the control group. There had no difference of the level of PGC-1α between the two groups. In vitro study, compared with the control groups, the level of triglyceride and the concentration of MDA in the model groups were increased and the activity of SOD as well as the expression of PGC-1α mRNA were decreased; When the final concentration of metformin is 7.5 mmol/l, the level of triglyceride and MDA were decreased as well as the activity of SOD and the expression of PGC-1α mRNA were increased compared with the model group. Conclusion: Metformin can adjust the expression of PGC-1α and the level of oxidative stress which can decrease the fat accumulation, Our results thus identify selective modulation of hepatic PGC-1α functions as a novel mechanism involved in the therapeutic action of metformin.
Highlights
With the improvement of people’s living standard and the change of lifestyle as well as population aging, the incidence of non-alcoholic fatty liver disease (NAFLD) in China is increasing gradually [1,2,3]
The level of MDA in the serum were measured by thiobarbituric acid method (TBA), the determination of superoxide dismutase (SOD) was by xanthine oxidation method (XTO)
The reason of this result may be due to the complexity of human body system and the difference of the detection method, but by vitro experiments we concluded that the decrease of the expression of PGC-1α may play an important role in the pathogenesis of NAFLD
Summary
With the improvement of people’s living standard and the change of lifestyle as well as population aging, the incidence of non-alcoholic fatty liver disease (NAFLD) in China is increasing gradually [1,2,3]. NAFLD is associated with increased risk of inflammation, cardiovascular disease [6,7] as well as insulin resistance (IR) and type 2 diabetes [8]. The pathogenesis of NAFLD is not clearly understood, it is known that insulin resistance assumes a pivotal role and it is generally regarded as the hepatic component of the metabolic syndrome (MetS) [9]. Drugs which can improve insulin sensitivity are widely used because insulin resistance play an important role in the pathophysiology of NAFLD [10]. The exact mechanisms of action are not fully understood, but probably involve the activation of AMPK, which results in the suppression of the production of glucose [17], cholesterol, and triglycerides, and stimulation of fatty acid oxidation [18]
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