Chronic activation of liver X receptor induces beta-cell apoptosis through hyperactivation of lipogenesis - Liver X receptor-mediated lipotoxicity in pancreatic beta-cells

Abstract

Liver X receptor (LXR)α and LXRβ play important roles in fatty acid metabolism and cholesterol homeostasis. Although the functional roles of LXR in the liver, intestine, fat, and macrophages are well established, its role in pancreatic β-cells has not been clearly defined. In this study, we revealed that chronic activation of LXR contributes to lipotoxicity-induced β-cell dysfunction. We observed significantly elevated expression of LXR in the islets of diabetic rodent models, including fa/fa ZDF rats, OLETF rats, and db/db mice. In primary pancreatic islets and INS-1 insulinoma cells, activation of LXR with a synthetic ligand, T0901317, stimulated expression of the lipogenic genes ADD1/SREBP1c, FAS, and ACC and resulted in increased intracellular lipid accumulation. Moreover, chronic LXR activation induced apoptosis in pancreatic islets and INS-1 cells, which was synergistically promoted by high glucose conditions. Taken together, we suggest lipid accumulation caused by chronic activation of LXR in β-cells as a possible cause of β-cell lipotoxicity, a key step in the development of type 2 diabetes.