Molecular decodification of gymnemic acids from Gymnema sylvestre. Discovery of a new class of liver X receptor antagonists

• Gymnemic acids were isolated and evaluated on NRs involved in glucose and lipid homeostasis.
• Gymnemic acids are potent and selective antagonists for the β isoform of LXR.
• Gymnemagenin is a potent and selective antagonist of β isoform of LXR.
• Gymnestrogenin is demonstrated a dual LXRα/β antagonist decreasing lipid accumulation in liver.
• This study substantiates the use of Gymnema sylvestre in LXR mediated dislypidemic diseases.

The individual chemical components of commercial extract of Gymnema sylvestre, a medicinal plant used in the traditional systems of the Indian medicine for its antidiabetic and hypolipidemic properties, were isolated and evaluated for their capability to act as modulators of nuclear and membrane receptors involved in glucose and lipid homeostasis.The study disclosed for the first time that individual gymnemic acids are potent and selective antagonists for the β isoform of LXR. Indeed the above activity was shared by the most abundant aglycone gymnemagenin (10) whereas gymnestrogenin (11) was endowed with a dual LXRα/β antagonistic profile. Deep pharmacological investigation demonstrated that gymnestrogenin, reducing the expression of SREBP1c and ABCA1 in vitro, is able to decrease lipid accumulation in HepG2 cells. The results of this study substantiate the use of G. sylvestre extract in LXR mediated dislypidemic diseases.