Abstract
Purpose: Metformin is one of the most popular drugs tested against nonalcoholic fatty liver disease (NAFLD). The present study aimed to investigate whether calcium-vitamin D3 cosupplementation will intensify the effect of metformin on the prevention of high-fat, high-fructose (HFFr) diet-induced hepatic steatosis.Methods: Male wistar rats (210±16 g) were assigned into the following seven groups: a Control group to receive a standard chow and six HFFr-fed groups to receive diets containing either normal (0.5% calcium and 1000 IU/kg vitamin D3) or high amount of calcium and vitamin D3 (2.4% calcium and 10000 IU/kg vitamin D3) (CaD), in combination with gastric gavage administration of either saline or 25 or 200 mg/kg body weight/day metformin. After 60 days, rats were assessed with respect to their anthropometric, metabolic and hepatic parameters, as well as their hepatic AMP-activated protein kinase (AMPK) phosphorylation.Results: Metformin and CaD, either alone or in combination, caused a significant reduction in HFFr diet-induced high serum aspartate aminotransferase (AST), hepatic steatosis and lipid accumulation without effect on insulin resistance and AMPK phosphorylation. In addition, slightly (and non-significantly) better effects of the combination in ameliorating steatosis and hepatic cholesterol content were observed.Conclusion: Taken together, our results suggest that metformin and CaD could protect against the onset of HFFr diet-induced NAFLD in an insulin and AMPK-independent manner, without any marked additional benefits of their combination.
Highlights
Nonalcoholic fatty liver disease (NAFLD) has become the most common form of chronic liver disease in the world, which is characterized by abnormal triglyceride accumulation in hepatocytes, not due to excess alcohol consumption or other causes of secondary hepatic steatosis.[1,2] A growing body of evidence suggests a bidirectional relationship between nonalcoholic fatty liver disease (NAFLD) and components of metabolic syndrome,[3,4] insulin resistance may still play an important role in the pathogenesis of NAFLD.[5]
The present study aimed to investigate whether calcium-vitamin D3 cosupplementation will intensify the effect of metformin on the prevention of high-fat, highfructose (HFFr) diet-induced hepatic steatosis
A growing body of evidence suggests a bidirectional relationship between NAFLD and components of metabolic syndrome,[3,4] insulin resistance may still play an important role in the pathogenesis of NAFLD.[5]
Summary
Nonalcoholic fatty liver disease (NAFLD) has become the most common form of chronic liver disease in the world, which is characterized by abnormal triglyceride accumulation in hepatocytes, not due to excess alcohol consumption or other causes of secondary hepatic steatosis.[1,2] A growing body of evidence suggests a bidirectional relationship between NAFLD and components of metabolic syndrome,[3,4] insulin resistance may still play an important role in the pathogenesis of NAFLD.[5]. The activation of AMPK in the liver could both induce catabolic pathways, such as β-oxidation of fatty acids, and suppress anabolic pathways like lipogenesis, potentially leading to reduced hepatic steatosis.[8,9] As some studies have shown that metformin could protect against the development of steatosis in animal models,[10,11] human studies are controversial.[12]. There is some evidence that vitamin D could be a natural insulin sensitizer, especially in combination with calcium.[13,14] Dietary calcium or VitD3 (cholecalciferol) intake, as well as calcitriol administration have been shown to prevent adiposity, insulin resistance[14,15] and hepatic fatty changes[16,17] and to be related to AMPK activation in different tissues in animal models.[18,19] On the
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