Synergistic Transcriptional Activation of Human Acyl-coenzyme A: Cholesterol Acyltransterase-1 Gene by Interferon-γ and All-trans-Retinoic Acid THP-1 Cells

Abstract

Acyl-coenzyme A:cholesterol acyltransferase (ACAT) is an intracellular enzyme involved in cellular cholesterol homeostasis and in atherosclerotic foam cell formation. Human ACAT-1 gene contains two promoters (P1 and P7), each located in a different chromosome (1 and 7) (Li, B. L., Li, X. L., Duan, Z. J., Lee, O., Lin, S., Ma, Z. M., Chang, C. C., Yang, X. Y., Park, J. P., Mohandas, T. K., Noll, W., Chan, L., and Chang, T. Y. (1999) J. Biol Chem. 274, 11060-11071). Interferon-γ (IFN-γ), a cytokine that exerts many pro-atherosclerotic effects in vivo, causes up-regulation of ACAT-1 mRNA in human blood monocyte-derived macrophages and macrophage-like cells but not in other cell types. To examine the molecular nature of this observation, we identified within the ACAT-1 P1 promoter a 159-base pair core region. This region contains 4 Spl elements and an IFN-γ activated sequence (GAS) that overlaps with the second Spl element. In the monocytic cell line THP-1 cell, the combination of IFN-γ and all-trans-retinoic acid (a known differentiation agent) enhances the ACAT-1 P1 promoter but not the P7 promoter. Additional experiments showed that all-trans-retinoic acid causes large induction of the transcription factor STAT1, while IFN-γ causes activation of STAT1 such that it binds to the GAS/Spl site in the ACAT-1 P1 Pl promoter. Our work provides a molecular mechanism to account for the effect of IFN-γ in causing transcriptional activation of ACAT-1 in macrophage-like cells.