Identification of an IL-6 response element in the human LCAT promoter.
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.
Feister
Hilary A
HA
Cardiovascular Pharmacology, Pfizer Global Research and Development, Ann Arbor, MI 48105, USA. hilary.feister@pfizer.com
Auerbach
Bruce J
BJ
Cole
Lisa A
LA
Krause
Brian R
BR
Karathanasis
Sotirios K
SK
D001665:Binding Sites; D004268:DNA-Binding Proteins / Q000378:metabolism; D006801:Humans; D007375:Interleukin-1 / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism*; D007862:Phosphatidylcholine-Sterol O-Acyltransferase / Q000235:genetics*; D011401:Promoter Regions, Genetic; D020218:Response Elements; D050796:STAT3 Transcription Factor; D015534:Trans-Activators / Q000378:metabolism; D015854:Up-Regulation
D004268:DNA-Binding Proteins; D007375:Interleukin-1; D015850:Interleukin-6; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D015534:Trans-Activators; D007862:Phosphatidylcholine-Sterol O-Acyltransferase