Cholesterol Regulation by Nuclear Receptor Trio

Abstract

Conversion of cholesterol to bile acids constitutes an important pathway for excretion of cholesterol and for generation of the bile acids themselves, which promote absorption of dietary cholesterol and fat-soluble vitamins. Accordingly, synthesis of bile acids is tightly regulated by feed-forward and feedback control mechanisms. A key step is regulated synthesis of cytochrome P-450 7A1 (CYP7A1), which catalyzes a rate-limiting step in biosynthesis of bile acids. The nuclear receptor FXR (farnesoid X receptor) is a bile acid receptor, but its role in feedback inhibition of expression of CYP7A1 has not been clear. Now papers by Lu et al . and Goodwin et al . show that FXR works by directly increasing expression of another nuclear receptor called SHP (for short heterodimer partner). SHP lacks a DNA-binding domain and inhibits activity of other nuclear receptors when it heterodimerizes with them. In this case, SHP binds yet another nuclear receptor, LRH-1 (liver receptor homolog 1), and attenuates the stimulatory action of LRH-1 on the CYP7A1 promoter. This regulatory cascade of nuclear receptors is apparently no fluke. The same strategy applies in regulation of the ecdysone receptor in Drosophila where one nuclear receptor causes expression of an inhibitory nuclear receptor lacking a DNA binding domain, which in turn represses the activity of a third nuclear receptor. Lu, T.T., Makishima, M., Repa, J.J., Schoonjans, K., Kerr, T.A., Auwerx, J., and Mangelsdorf, D.J. (2000) Molecular basis for feedback regulation of bile acid synthesis by nuclear receptors. Mol. Cell 6 : 507-515. [Online Journal] Goodwin, B., Jones, S.A., Price, R.R., Watson, M.A., McKee, D.D., Moore, L.B., Galardi, C., Wilson, J.G., Lewis, M.C., Roth, M.E., Maloney, P.R., Willson, T.M., and Kliewer, S.A. (2000) A regulatory cascade of the nuclear receptors FXR, SHP-1, and LRH-1 represses bile acid biosynthesis. Mol. Cell 6 : 517-526. [Online Journal]