Effect of Melatonin as an Antioxidant Drug to Reverse Hepatic Steatosis: Experimental Model

Abstract

Introduction. The hepatic steatosis of the nonalcoholic origin or NAFLD is increasing at present, particularly in Western countries, parallel to the increase in obesity, constituting one of the most prevalent hepatic processes in the Western society. Melatonin has been successfully tested in experimental models in mice as a drug capable of reversing steatosis. The effect of melatonin on fat metabolism can be summarized as a decrease in lipid peroxidation and a decrease in oxidative stress, biochemical phenomena intimately related to fat deposition in the hepatocyte. There are hardly any studies in large animals. Objective. In this study, we investigate the effects of melatonin administered orally at a dose of 10 mg/kg/day to reverse established hepatic steatosis induced by a special diet in a porcine animal model. Materials and Methods. We analyze the parameters of oxidative stress: malondialdehyde (MDA), 4-hydroxyalkenals (4-HDA), and carbonyls, degree of fat infiltration (analyzed by direct vision by a pathologist and by means of a computer program of image treatment), and serological parameters of lipid metabolism and hepatic damage. These parameters were analyzed in animals to which hepatic steatosis was induced by means of dietary modifications. Results. We have not been able to demonstrate globally a beneficial effect of melatonin in the improvement or reversal of liver steatosis once established, induced by diet in a porcine animal model. However, we have found several signs of improvement at the histological level, at the level of lipid metabolism, and at the level of oxidative stress parameters. We have verified in our study that, in the histological analysis of the liver sample by means of the program image treatment (free of subjectivity) of the animals that continue with the diet, those that consume melatonin do not increase steatosis as much as those that do not consume it significantly (p=0.002). Regarding the parameters of oxidative stress, MDA modifies in a significant manner within the group of animals that continue with the diet and take melatonin (p=0.004). As for lipid metabolism, animals that maintain the steatotic diet and take melatonin lower total and LDL cholesterol levels and increase HDL levels, although these results do not acquire statistical significance. Conclusions. In this study, it has not been possible to demonstrate a beneficial effect of melatonin in the improvement or reversal of liver steatosis once established and induced by diet in the porcine model. It is true that signs of improvement have been found at the histological level, at the level of lipid metabolism, and at the level of oxidative stress phenomena, when comparing animals with established steatosis that are treated with melatonin with those who do not take it. This work is the first study conducted in a large animal model in which the effect of melatonin is studied as a treatment in the reversal of established hepatic steatosis.

Hepatic galectin-3 is associated with lipid droplet area in non-alcoholic steatohepatitis in a new swine model

“…The availability of a large animal model of NAFLD with initial NASH in a short period may be of particular interest to understand the onset of NAFLD and its progression to NASH, to explore new treatments for this ailment 41 and to better characterize the steatotic liver for transplant procedures 36 . In these two experiments, 20 animals were provided the steatotic diet and all of them reached NAFLD according FLIP algorithm.…”

Association between Melatonin Value and Interleukins1B, -18, and -33 Levels in Patients with Different Stages of Non-Alcoholic Fatty Liver Disease

“…Indeed, melatonin were used as treatment of NAFLD, previous reports illustrated that melatonin therapy decreased the severity of steatosis, inhibited the immigration of inflammatory cells, protected hepatic cells from damage, and also reduced serum and tissue inflammatory cytokines concentration. 25 - 27 …”

Melatonin ameliorates hepatic steatosis by inhibiting NLRP3 inflammasome in db/db mice

“… 14 , 28 It is noteworthy that melatonin administration exhibited distinct improvements on histology in diet-induced NAFLD mice or pigs. 29 , 30 There are barely any studies on db/db diabetic mice that verify the therapeutic action of melatonin for NAFLD. In this study, we found that melatonin slightly reduced blood glucose and ameliorated dyslipidemia, hepatic enzymes, and MMP.…”