The Eeffect of Metformin Combined with Calcium-Vitamin D3 Against Diet-Induced Nonalcoholic Fatty Liver Disease

Introduction 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 although insulin resistance may still play an important role in the pathogenesis of NAFLD.5 It is believed that insulin resistance and adiposity are associated with an imbalance between delivery and export of free fatty acid to the liver.1,5 Therefore, it is not surprising that several studies have investigated the efficacy of natural or pharmacological insulin sensitizers on the prevention and management of NAFLD. Metformin is believed to exert its anti-diabetic effects through inhibition of mitochondrial respiratory chain complex I,6,7 resulting in a fall in the ATP/AMP ratio and activation of AMP-activated protein kinase (AMPK), a master kinase regulating cellular energy homeostasis.8 The activation of AMPK in the liver could both induce catabolic pathways, such as ß-oxidation of fatty acids, and suppress anabolic pathways like lipogenesis, thus 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 however human studies are controversial.12 There is now 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 resistance14,15 and hepatic fatty changes16,17 and to be related to AMPK activation in different tissues in animal models.18,19 On the other hand, Shalata et al2 reported that vitamin D could intensify the effects of sitaglibtin/metformin drugs on treatment of steatosis and on decreasing hepatic triglyceride and malondialdehyde (MDA) content. The rats in the CaD+S group exhibited clearly higher levels of serum HDL-C compared to the groups receiving recommended levels of calcium and vitamin D3. [...]the levels of serum CTRP3 was significantly higher in the +Met200 group compared to the other groups (except the +CaD+Met200 group). [...]in the present study, the HFFr+S rats showed higher levels of serum ALT and AST compared to the Control group (131