Identification of Alverine and Benfluorex as HNF4α Activators

Abstract

The principal finding of this study is that two drugs, alverine and benfluorex, used in vastly different clinical settings and previously unknown to share mechanistic or structural similarity, activated the nuclear receptor transcription factor HNF4α. 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 Benfluorex was withdrawn from the market recently because of serious cardiovascular side effects related to fenfluramine-like activity.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 HNF4α. This novel mechanism of action should lead to a reinterpretation of previous studies with these drugs and suggests a path towards the development of therapies for diseases such as inflammatory bowel and diabetes that may respond to HNF4α activators.

Hnf4α is involved in the regulation of vertebrate LC-PUFA biosynthesis: insights into the regulatory role of Hnf4α on expression of liver fatty acyl desaturases in the marine teleost Siganus canaliculatus

“…Alverine and benfluorex were activators of human HNF4α and could increase HNF4α mRNA level in vitro, whereas BI6015 had the opposite effect compared to the above two chemicals and was antagonist to human HNF4α (Kiselyuk et al, 2012b;Lee et al, 2013).…”

Hnf4α Is Involved in LC-PUFA Biosynthesis by Up-Regulating Gene Transcription of Elongase in Marine Teleost Siganus canaliculatus

“…As a ligand-dependent TF, long chain fatty acids such as ALA, EPA and DHA are endogenous ligands for HNF4α, so binding to this nuclear receptor suppressed its activation to the target genes [ 36 ]. Some chemical ligands such as those used in the present study, i.e., Alverine and Benfluorex, could increase hnf4α gene expression and activate this TF as a ligand [ 37 ]. In relation to recent research on the regulation of elovl5 in the teleost Larimichthys crocea and Epinephelus coioides , feed-back regulation in LC-PUFA biosynthesis from the process of dietary lipid to fish metabolism and LC-PUFA (EPA and DHA) to hepatocytes was carried out through another nuclear receptor LXRα and its downstream target SREBP-1 [ 21 , 23 ].…”

Insulin acts as a repressive factor to inhibit the ability of PAR2 to induce islet cell transdifferentiation

“…Figure 1). [12][13][14]9 2fLI is a modified peptide derived from the N-terminus of PAR2 that mimics the effect of the N-terminal peptide that is released by proteolytic cleavage and serves as the physiological activators of PAR2. 2fLI is highly specific for PAR2 as determined by a lack of effect in the PAR2 knockout mouse.…”

“…Candidates were selected from known secreted products of b¡cells that had receptors expressed on a¡cells. Factors were incubated with T6PNE cells for 4 days in the presence of 0.5 mmol/l tamoxifen plus 2fLI as we have done previously [12][13][14]. a.…”