Identification of Alverine and Benfluorex as HNF4α Activators

The principal finding of this study is that two drugs, alverine and benfluorex, used in vastly different clinical settings, activated the nuclear receptor transcription factor HNF4 alpha. Both were hits in a high-throughput screen for compounds that reversed the inhibitory effect of the fatty acid palmitate on human insulin promoter activity. Alverine is used in the treatment of irritable bowel syndrome, while benfluorex (Mediator) was used to treat hyperlipidemia and type II diabetes. Benfluorex was withdrawn from the market recently because of serious cardiovascular side effects related to fenfluramine-like activity. Strikingly, alverine and benfluorex have a previously unrecognized structural similarity, consistent with a common mechanism of action. Gene expression and biochemical studies revealed that they both activate HNF4 alpha. This novel mechanism of action should lead to a reinterpretation of previous studies with these drugs and suggests a path toward the development of therapies for diseases such as inflammatory bowel and diabetes that may respond to HNF4 alpha activators.