A New Approach to Cholesterol Regulation?

Abstract

Otte et al. took a close look at a human pseudogene and discovered a novel mammalian nuclear receptor that may play a role in regulating nonprimate cholesterol metabolism. Cholesterol homeostasis is maintained through three distinct pathways: synthesis from acetate, uptake from the intestine, and catabolism into bile acids. Dysregulation leads to cholesterol accumulation and such pathological conditions as atherosclerosis and gallstones. The breakdown of cholesterol into bile acids is regulated through transcriptional mechanisms mediated through nuclear receptors. A DNA sequence showing homology to the farnesoid X receptor (FXR), a nuclear receptor that binds bile acids and suppresses cholesterol degradation, designated FXRβ, was identified as a pseudogene after the sequencing of the human genome. Otte et al. used reverse-transcriptase-polymerase chain reaction (RT-PCR) to reveal FXRβ mRNAs that show continuous open reading frames in mice, rats, rabbits, and dogs. FXRβ, which displayed splice variants that differed in their ligand- and DNA binding domains, was ubiquitously expressed in embryonic tissue, as well as in adult liver, reproductive tissues, and heart. Constitutively active FXRβ constructs transactivated reporter genes containing nuclear receptor DNA response elements; other FXRβ constructs heterodimerized with a human retinoic acid X receptor. Unlike the evolutionarily related FXR, which binds bile acids, FXRβ bound lanosterol, an intermediate in the cholesterol synthetic pathway. Lanosterol promoted interactions between FXRβ and a nuclear receptor coactivator and stimulated FXRβ-dependent transcriptional activation. The activation of FXRβ by lanosterol may imply that it participates in the regulation of cholesterol biosynthesis in mammalian nonprimates. K. Otte, H. Kranz, I. Kober, P. Thompson, M. Hoefer, B. Haubold, B. Remmel, H. Voss, C. Kaiser, M. Albers, Z. Cheruvallath, D. Jackson, G. Casari, M. Koegl, S. Pääbo, J. Mous, C. Kremoser, U. Deuschle, Identification of farnesoid X receptor β as a novel mammalian nuclear receptor sensing lanosterol. Mol. Cell. Biol. 23 , 864-872 (2003). [Abstract] [Full Text]