Discovery of a novel therapeutic agent for NAFLD derived from VDR-silent vitamin D derivatives

Enhanced de novo lipogenesis mediated by sterol regulatory element-binding protein (SREBP) is considered to be involved in pathogenesis of NAFLD and inhibition of SREBP may be an effective therapeutic strategy. A chemical library of endogenous molecules was screened and 25-hydroxyvitamin D (25OHD) was identified as an inhibitor of SREBP activation. Unlike sterols and other SREBP inhibitors, 25OHD impairs SREBP activation by inducing proteolytic processing and ubiquitin-mediated degradation of SREBP cleavage-activating protein (SCAP), thereby decreasing SREBP levels independently of the vitamin D receptor (VDR). Based on this finding, we designed and synthesized a series of vitamin D derivatives to search for a drug-like small molecule that suppresses the SREBP-induced lipogenesis without affecting the VDR-controlled calcium homeostasis in vivo. Evaluation of the derivatives in cultured cells and mice led to the discovery of A-ring substituted 25OHD derivatives as VDR-silent SREBP inhibitors and to the development of KK-052, the first vitamin D-based SREBP inhibitor that has been demonstrated to mitigate hepatic lipid accumulation without calcemic action in mice. KK-052 maintained the ability of 25OHD to induce the degradation of SREBP and its escort protein SCAP but lacked in the VDR-mediated activity. KK-052 serves as a valuable compound for NAFLD and may represent an unprecedented translational opportunity of synthetic vitamin D analogues.