Glucosamine-supplementation promotes endoplasmic reticulum stress, hepatic steatosis and accelerated atherogenesis in apoE−/− mice

OBJECTIVES: To determine the effects of glucosamine-supplementation on endoplasmic reticulum (ER) stress levels and atherogenesis, and to investigate the potential role of glucosamine in hyperglycemia-associated accelerated atherosclerosis. METHODS: Five week old apolipoprotein E-deficient (apoE-/-) mice were provided with normal drinking water or water supplemented with 5% glucosamine (w/v) or 5% mannitol (w/v). To induce hyperglycemia, a separate group of apoE-/- mice received multiple low dose injections of streptozotocin (STZ). All mice were provided with a standard chow diet and were euthanized at 15 weeks of age. Hepatic and vascular ER stress levels and atherosclerotic lesion area at the aortic root were determined. RESULTS: STZ-induced hyperglycemic and glucosamine-supplemented mice had significantly larger and more advanced atherosclerotic lesions than control mice. Indications of ER stress were increased in the livers and atherosclerotic lesions of hyperglycemic and glucosamine-supplemented mice but not in the controls. In glucosamine-supplemented mice accelerated atherosclerosis was independent of detectable changes in blood glucose concentration, glucose tolerance, plasma insulin, or plasma lipid levels. CONCLUSION: Similar to hyperglycemia, glucosamine-supplementation promotes ER stress, hepatic steatosis and accelerated atherosclerosis. These findings support a model by which hyperglycemia promotes hepatic and vascular complications via a glucosamine intermediate.