Grant: Operating Grant

We have uncovered an exciting new application of 1,25-dihydroxyvitamin D3 (1,25VD3), the active component arising from vitamin D intake, towards cholesterol lowering in mice. We observed that 1,25VD3, when administered for binding to the vitamin D receptor (VDR), resulted in suppression of a repressive receptor known as the small heterodimer partner (SHP). Suppression of the SHP led to removal of repression of cholesterol 7alpha-hydroxylase (CYP7A1), the key enzyme responsible for cholesterol degradation and lowering of cholesterol in serum and liver. We plan to study the mechanism of action of the VDR on other nuclear receptors: FXR (farnesdoid X receptor, normally a stimulator of SHP and/or intestinal FGF15, another repressor of CYP7A1), SHP, or other nuclear receptors in cholesterol lowering. We plan to use gene knockout mice that lack FXR or SHP and the cholesterol transport genes - the low density lipoprotein receptor (LDLR) and apolipoprotein E (apoE), an enzyme essential for normal catabolism of triglyceride-rich lipoprotein constituents. In our planned studies, mice will be given a high fat/high cholesterol diet for us to assess the effectiveness of 1,25VD3 treatment on altered SHP and CYP7A1 levels in cholesterol lowering. We will identify the molecular mechanism and show that 1,25VD3 and the VDR regulate CYP7A1. We further plan to synthesize nontoxic, new compounds that bind to the VDR with optimized cholesterol lowering properties, including lithocholic acid derivations as alternates of 1,25VD3, via computer design (molecular modeling). Ideally, these compounds would bind strongly to the VDR and not to FXR and are nontoxic. We plan to examine the properties of 1,25VD3 and these new agents (lithocholic acid derivatives) in vivo with the statins (cholesterol lowering medication) to appraise their usefulness when these are used singly or in combination. Our work will firmly establish that the VDR is a target for cholesterol lowering.