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Hyodeoxycholic acid derivatives as liver X receptor ? and G-protein-coupled bile acid receptor agonists.

ABSTRACT: Bile acids are extensively investigated for their potential in the treatment of human disorders. The liver X receptors (LXRs), activated by oxysterols and by a secondary bile acid named hyodeoxycholic acid (HDCA), have been found essential in the regulation of lipid homeostasis in mammals. Unfortunately, LXR? activates lipogenic enzymes causing accumulation of lipid in the liver. In addition to LXRs, HDCA has been also shown to function as ligand for GPBAR1, a G protein coupled receptor for secondary bile acids whose activation represents a promising approach to liver steatosis. In the present study, we report a library of HDCA derivatives endowed with modulatory activity on the two receptors. The lead optimization of HDCA moiety was rationally driven by the structural information on the binding site of the two targets and results from pharmacological characterization allowed the identification of hyodeoxycholane derivatives with selective agonistic activity toward LXR? and GPBAR1 and notably to the identification of the first example of potent dual LXR?/GPBAR1 agonists. The new chemical entities might hold utility in the treatment of dyslipidemic disorders.

SUBMITTER: De Marino S

PROVIDER: S-EPMC5324103 | biostudies-literature | 2017 Feb

REPOSITORIES: biostudies-literature

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Hyodeoxycholic acid derivatives as liver X receptor α and G-protein-coupled bile acid receptor agonists.

De Marino Simona S Carino Adriana A Masullo Dario D Finamore Claudia C Marchianò Silvia S Cipriani Sabrina S Di Leva Francesco Saverio FS Catalanotti Bruno B Novellino Ettore E Limongelli Vittorio V Fiorucci Stefano S Zampella Angela A

Scientific reports 20170224

Bile acids are extensively investigated for their potential in the treatment of human disorders. The liver X receptors (LXRs), activated by oxysterols and by a secondary bile acid named hyodeoxycholic acid (HDCA), have been found essential in the regulation of lipid homeostasis in mammals. Unfortunately, LXRα activates lipogenic enzymes causing accumulation of lipid in the liver. In addition to LXRs, HDCA has been also shown to function as ligand for GPBAR1, a G protein coupled receptor for seco ...[more]

PMID: 28233865

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Dataset Information

Hyodeoxycholic acid derivatives as liver X receptor ? and G-protein-coupled bile acid receptor agonists.

Publications

Hyodeoxycholic acid derivatives as liver X receptor α and G-protein-coupled bile acid receptor agonists.

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