A retinoic acid-responsive element in the apolipoprotein AI gene distinguishes between two different retinoic acid response pathways.

The gene coding for apolipoprotein AI, a plasma protein involved in the transport of cholesterol and other lipids in the plasma, is expressed predominantly in liver and intestine. Previous work in our laboratory has shown that hepatocyte-specific expression is determined by synergistic interactions between transcription factors bound to three separate sites, sites A (-214 to -192), B (-169 to -146), and C (-134 to -119), within a powerful liver-specific enhancer located in the region -222 to -110 nucleotides upstream of the apolipoprotein AI gene transcription start site (+1). In this study, it was found that site A is a highly selective retinoic acid-responsive element (RARE) that responds preferentially to the recently identified retinoic acid receptor RXR alpha over the previously characterized retinoic acid receptors RAR alpha and RAR beta. Control experiments indicated that a RARE in the regulatory region of the laminin B1 gene responds preferentially to RAR alpha and RAR beta over RXR alpha, while a previously described palindromic thyroid hormone-responsive element responds similarly to all three of these receptors. Gel retardation experiments showed that the activity of these RAREs is concordant with receptor binding. These results indicate that different RAREs may play a fundamental role in defining distinctive retinoic acid cellular response pathways and suggest that retinoic acid response pathways mediated by RXR alpha play an important role in cholesterol and retinoid transport and metabolism.