Attenuation of Experimental Cholesterol Gallstone Formation by Manganese Chloride in Mice: Role of NF-κβ Pathways

Abstract

Manganese (Mn), a trace element, has been documented to exert an important role in the metabolism of cholesterol. Cholesterol gallstone (CG) pathogenesis is directly linked to biliary cholesterol imbalance which could be due to diabetes complications or mismanagement. NF-κβ pathway, an inflammatory regulator, has been implicated in metabolic disease especially in the context of diabetes and gallstone formation. However, the management of cholesterol gallstones due to diabetes with trace elements is vague. This study investigates the probable role of manganese during CG formation due to diabetes complications. Eighty female Swiss mice were grouped: I (control), II (untreated CG), III and IV (normal mice treated 0.37 mg/kg and 0.74 mg/kg Mn, respectively), V and VI (CG treated 0.37 mg/kg and 0.74 mg/kg Mn, respectively), and VII and VIII (CG treated 75 mg/7 kg and 350 mg/kg aspirin, respectively). Experimental CG was induced with cholesterol-rich diets after alloxan-induced diabetes. On sacrifice, blood collected was evaluated for complete hematological analysis and biochemistry while the excised liver was assayed for biochemical variables. Results were subjected to one-way ANOVA values were expressed as Mean ± SEM and significant at p ≤ 0.05. Manganese treatment significantly increased packed cell volume, RBC count, and hemoglobin with decreased platelet and leukocyte counts, liver enzymes (AST, ALT, and ALP), BUN, and creatinine levels in CG groups compared with untreated CG. Blood glucose, plasma low-density lipoproteins, and liver malodialdehyde levels were significantly reduced while liver nitric-oxide, sulfhydryl, and glutathione levels increased significantly in manganese-treated groups compared with untreated CG. Manganese significantly increased fecal iron contents in normal mice by the 2nd week. Hepatocytes and gallbladder histology appear normal in manganese-treated groups. Liver NF-Kβ immunoreactivity was downregulated in manganese-treated CG groups. Manganese attenuated experimental hyperglycemia-induced cholesterol gallstone by ameliorating liver oxidative stress and NF-Kβ inflammatory pathway.

Keywords: Anti-oxidative and hepato-biliary; Cholesterol gallstone; Lipid homeostasis; Manganese chloride.