TNF-related apoptosis-inducing ligand (TRAIL) protects against diabetes and atherosclerosis in Apoe -/- mice

Aims/hypothesis: TNF-related apoptosis-inducing ligand (TRAIL) is implicated in the regulation of diabetes and is reduced in patients with cardiovascular disease. Although TRAIL receptors are widespread, and TRAIL can promote cell proliferation and apoptosis, it is not known how TRAIL might protect against diabetes and atherosclerosis. Methods: We examined the development of atherosclerosis and diabetes in Apoe ^-/-, Trail (also known as Tnfsf10) ^-/- Apoe ^-/- and Trail ^-/- mice that were fed a high-fat diet. Plasma cholesterol, triacylglycerol, glucose and insulin, as well as changes in various metabolic enzymes and regulators were assessed. Glucose and insulin tolerance tests were performed. Pancreatic islets were examined for insulin and beta cell dysfunction (apoptosis and macrophage infiltration). Results: Compared with Apoe ^-/- mice, Trail ^-/- Apoe ^-/- and Trail ^-/- mice exhibited several features of diabetes, including increased weight, hyperglycaemia, reduced plasma insulin, impaired glucose tolerance, beta cell dysfunction, reduced islet insulin, macrophage infiltration and increased apoptosis. Trail ^-/- Apoe ^-/- mice had increased plasma cholesterol, triacylglycerol, and VLDL- and LDL-cholesterol, and increased expression of genes involved in cholesterol synthesis and lipogenesis. Trail ^-/- Apoe ^-/- mice also had increased atherosclerosis, with several features of plaque instability. Conclusions/interpretation: We show for the first time that TRAIL deficiency promotes numerous features of diabetes that are typical of human disease, and are associated with reduced insulin and pancreatic inflammation/apoptosis. TRAIL also regulates cholesterol and triacylglycerol homeostasis in Apoe ^-/- mice by increasing the expression of genes involved in (1) cholesterol synthesis and absorption, and (2) triacylglycerol production.