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Journal of Lipid Research, Vol. 47, 1463-1477, July 2006
Copyright © 2006 by American Society for Biochemistry and Molecular Biology


* Departments of Medical Genetics and Genome Sciences, University of Washington, Seattle, WA
Department of Cell Biology, Neurobiology, and Anatomy, Medical College of Wisconsin, Milwaukee, WI
Published, JLR Papers in Press, April 7, 2006.
1 To whom correspondence should be addressed. e-mail: 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. However, little is known about the factors responsible for HL expression. Here, we report that the human hepatic lipase gene (LIPC) promoter is regulated by hepatocyte nuclear factor 4
(HNF4
), peroxisome proliferator-activated receptor
coactivator-1
(PGC-1
), apolipoprotein A-I regulatory protein-1 (ARP-1), and hepatocyte nuclear factor 1
(HNF1
). Reporter analysis showed that HNF4
directly regulates the LIPC promoter via two newly identified direct repeat elements, DR1 and DR4. PGC-1
is capable of stimulating the HNF4
-dependent transactivation of the LIPC promoter. ARP-1 displaces HNF4
from the DR1 site and blocks its ability to activate the LIPC promoter. Induction by HNF1
requires the HNF1 binding site and upon cotransfection with HNF4
leads to an additive effect. In addition, the in vivo relevance of HNF4
in LIPC expression is shown by the ability of the HNF4
antagonist Medica 16 to repress endogenous LIPC mRNA expression. Furthermore, disruption of Hnf4
in mice prevents the 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.
Abbreviations: ARP-1, apolipoprotein A-I regulatory protein-1; ChIP, chromatin immunoprecipitation; COUP-TFII, chicken ovalbumin upstream promoter transcription factor II; CYP7A1, cholesterol 7
-hydroxylase; DR, direct repeat; EMSA, electrophoretic mobility shift assay; FXR, farnesoid X receptor; HNF1
, hepatocyte nuclear factor 1
; HNF4
, hepatocyte nuclear factor 4
; LIPC, hepatic lipase gene; PGC-1
, peroxisome proliferator-activated receptor
coactivator-1
; RAR
, retinoic acid receptor
; RXR
, retinoid X receptor
; USF, upstream stimulatory factor; WCE, whole cell extract; WT, wild-type
Supplementary key words lipid metabolism nuclear receptors direct repeats hepatocyte nuclear factor 4
hepatocyte nuclear factor 1
apolipoprotein A-I regulatory protein-1 HuH7 cells transcription factor binding chromatin immunoprecipitation peroxisome proliferator-activated receptor
coactivator-1
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