Dysregulation of Hnf1b gene expression in cultured beta-cells in response to cytotoxic fatty acid.

CONTEXT: Increased levels of circulating fatty acids deriving from over-nutrition are thought to contribute to the progressive beta-cell failure associated with type 2 diabetes. Pancreatic beta-cells in culture are sensitive to exposure to long-chain saturated fatty acids (e.g. palmitate) which cause cytotoxicity, whereas the monounsaturated equivalents (e.g. palmitoleate) are cytoprotective. OBJECTIVES: In this study we sought to determine whether of members of the hepatocyte nuclear factor (HNF) family of transcription factors, which are mutated in familial, young-onset, monogenic beta-cell diabetes, could play a role in fatty acid-mediated cytotoxicity in cultured beta-cells. DESIGN: We used real-time PCR to determine whether hepatocyte nuclear factor gene expression was altered in response to palmitate exposure in the BRIN-BD11 beta-cell line. RESULTS: We found that the Hnf isoforms expressed in BRIN-BD11 cells are dysregulated by palmitate exposure. The expression of Hnf1b is specifically reduced by exposure to palmitate, and this response is prevented by co-incubation with palmitoleate. CONCLUSIONS: Down-regulation of Hnf1b gene expression accompanies palmitate-mediated cytotoxicity in cultured beta-cells.