The Oxysterol Receptor

Abstract

Studies of the regulation of cholesterol biosynthesis in mammalian cells have led to a model in which transcription of the mRNA for the regulatory enzyme, 3-hydroxy-3-methylglutaryl coenzyme A ((HMG-CoA) reductase, is controlled by an endogenous oxysterol metabolite(s) bound to a specific oxysterol receptor (1,2, Fig 1). Since this regulatory mechanism may be important in the control of HMG-CoA reductase enzyme levels in all cell types, its physiological role is distinctly different from those involving steroid hormones as regulators of gene expression. Nevertheless certain similarities and clear analogies with conventional hormone receptor models have guided our thinking. Initially the similarity was suggested by the high biological potencies of the oxysterols when added to cell cultures (3). Furthermore, the oxysterols do not directly inactivate the enzyme, but act to specifically repress HMG-CoA reductase synthesis by lowering the level of its mRNA (4,5). A cytosolic oxysterol receptor has now been identified (6–9) and the presence in cultured cells and in liver, in vivo, of oxysterol metabolites capable of repressing the reductase has been demonstrated (10,11). Thus the existence of the basic elements of the model has been established.