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Journal of Lipid Research, Vol. 43, 960-970, June 2002
Copyright © 2002 by Lipid Research, Inc.

Identification of an IL-6 response element in the human LCAT promoter

Hilary A. Feister^1,*, Bruce J. Auerbach^*, Lisa A. Cole, Brian R. Krause and Sotirios K. Karathanasis^*

^* Cardiovascular Pharmacology, Pfizer Global Research and Development, Ann Arbor, MI 48105
Department of Nutrition and Food Science, Wayne State University, Detroit, MI 48202
Esperion Therapeutics, Inc., Ann Arbor, MI 48108

¹ To whom correspondence should be addressed. e-mail: hilary.feister{at}pfizer.com

LCAT is a key enzyme of reverse cholesterol transport that is essential to maintain HDL-mediated lipid transport and cholesterol homeostasis. Alterations in LCAT expression have a profound effect on plasma HDL cholesterol concentrations. Previously LCAT mRNA and activity were shown to be regulated by several inflammatory cytokines, including the pleiotrophic cytokine interleukin-6 (IL-6). A series of full-length and sequential deletion LCAT promoter constructs were used to determine whether inflammatory stimuli affect LCAT transcription and to further identify functional, cytokine-responsive promoter regions that mediate this response. Using transfected HepG2 cells, results indicate that treatment with IL-6 induced a 2.5-fold activation of full-length LCAT promoter activity. A minimal (-1514 bp to -1508 bp) IL-6 response element with high sequence homology to the signal transducer and activator of transcription (STAT) family member, STAT3, was mapped within the distal promoter and shown to be sufficient to mediate the IL-6 response. Further, overexpression of STAT3 significantly enhanced the effect of IL-6 on LCAT promoter activity.

These data suggest that the IL-6 responsive transcription factor, STAT3, contributes to LCAT transcriptional regulation. The elucidation of distinct biochemical signaling pathways associated with inflammation may provide new insight into transcriptional regulation of genes involved in lipid metabolism.

Abbreviations: CRP, C-reactive protein; IFN-, interferon-; IL-6, interleukin-6; IL-1ß, interleukin-1ß; JAK, Janus kinase; LPS, lipopolysaccharide; NF-B, nuclear factor-B; SAA, serum amyloid A; SAF, sequence binding factor; SR-BI, scavenger receptor class B, type I; STAT, signal transducer and activators of transcription; TGF-ß, transforming growth factor; TNF-, tumor necrosis factor-

Supplementary key words inflammation • STAT3 • transcription • HDL cholesterol • signal transduction • interleukin-6 • lecithin:cholesterol acyltransferase

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