J. Lipid Res. Neurobiology of Lipids (ISSN1683-5506)
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A more recent version of this article appeared on July 1, 2006

Papers In Press, published online ahead of print April 7, 2006
J. Lipid Res., doi:10.1194/jlr.M600082-JLR200
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Submitted on February 16, 2006
Revised on April 3, 2006
Accepted on April 6, 2006

Transcriptional regulation of the human hepatic lipase (LIPC) gene promoter

Laura E. Rufibach, Stephen A. Duncan, Michele Battle, and Samir S. Deeb

Medical Genetics and Genome Sciences, University of Washington, Seattle, WA 98195

Corresponding Author: lewarner{at}u.washington.edu

Hepatic lipase (HL) plays a key role in the metabolism of plasma lipoproteins and its level of activity requires tight regulation given the association of both low and high levels with atherosclerosis and coronary artery disease (CAD). However, little is know about the factors responsible for HL expression. Here we report that the human HL gene (LIPC) promoter is regulated by hepatocyte nuclear factor-4alpha (HNF4alpha ), peroxisome proliferator-activated receptor gamma coactivator-1alpha (PGC-1alpha ), apolipoprotein A-I regulatory protein-1 (ARP-1), and hepatocyte nuclear factor-1alpha (HNF1alpha ). Reporter analysis showed that HNF4alpha directly regulates the LIPC promoter via two newly identified direct repeat elements, DR1 and DR4. The coactivator PGC-1alpha is capable of stimulating the HNF4alpha -dependent trans-activation of the LIPC promoter. ARP-1 displaces HNF4alpha from the DR1 site and blocks its ability to activate the LIPC promoter. Induction by HNF1alpha requires the HNF1 binding site and upon co-transfection with HNF4alpha leads to an additive effect. In addition, the in vivo relevance of HNF4alpha in LIPC expression is shown by the ability of the HNF4alpha antagonist Medica 16 to repress endogenous LIPC mRNA expression. Furthermore, disruption of Hnf4alpha in mice prevents expression of HL mRNA in liver. The overall effect these transcription factors have on HL expression will ultimately depend on the interplay between these various factors and their relative intracellular concentrations.


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