Therapeutic effect of the α-glucosidase inhibitor on diet-induced fatty liver disease in mice

Abstract

Non-alcoholic fatty liver disease (NAFLD) is a chronic metabolic disease associated with unhealthy lifestyle, especially unhealthy eating. Increased intake of glucose, fructose, or saturated fat increases hepatic de novo lipogenesis, a major mechanism of NAFLD development. α -glucosidase inhibitors (AGIs) are a class of antidiabetic agents that inhibit the conversion of polysaccharides to monosaccharides in the intestinal lumen. This function of AGIs is considered to be effective in the prevention and treatment of NAFLD. Although studies have reported that AGIs effectively prevent NAFLD in animal models, studies on the effects of AGIs in nondiabetic NAFLD models are still lacking. Furthermore, to the best of our knowledge, there are no published studies on the effects of AGIs in NAFLD model induced by a high-fat, high-fructose (HFHF) diet. Therefore, we examined the therapeutic effect of voglibose (an orally active AGI) on a HFHF diet-induced nondiabetic NAFLD mouse model. We also assessed the effectiveness of voglibose in combination with pioglitazone, a proven therapeutic agent for NAFLD. Seven-week-old male C57BL/6J mice were randomly divided into two groups: a normal chow diet and a HFHF diet groups. After 10 weeks, HFHF diet group was subdivided into four groups: HFHF-vehicle treated (HFHF), HFHF-voglibose treated (HFHF-V), HFHF-pioglitazone treated (HFHF-P), and HFHF-combination therapy (HFHF-C) groups. Each treatment was administered daily via oral gavage for 10 weeks. The normal chow diet group maintained the same diet with vehicle administration for the 10 weeks. After 20 weeks, HFHF group became obese and developed NAFLD, including hepatic steatosis, inflammation and fibrosis. Voglibose administration attenuated HFHF-induced hepatic steatosis and reduced proinflammatory and fibrotic markers in the liver. These effects were comparable to those of pioglitazone treatment. Combination therapy with voglibose and pioglitazone showed therapeutic effects similar to each monotherapy group but without any additive effects. In the HFHF-V group, gene expression and protein levels of hepatic lipogenesis markers, including sterol regulatory element-binding transcription factor-1 and carbohydrate response element binding protein, were significantly downregulated; HFHF-C group showed similar results. These findings indicate that voglibose ameliorated NAFLD by reducing hepatic de novo lipogenesis in the HFHF diet-induced nondiabetic NAFLD model. In the in vitro experiment, reducing the influx of glucose into hepatocytes significantly reduced hepatic steatosis and de novo lipogenesis even in the presence of sufficient fructose and fat, demonstrating the potential benefits of voglibose in HFHF diet-induced NAFLD. Hepatic expression of autophagy markers was improved in voglibose treated mice, which may also be beneficial for the treatment of NAFLD. In conclusion, voglibose robustly improved HFHF diet-induced NAFLD in mice, by suppressing hepatic de novo lipogenesis. Although combination therapy with voglibose and pioglitazone showed significant therapeutic effects, there were no additive or synergistic effects due to the combination therapy in this experiment.