Faculty Collaboration Database

Transcriptional regulation of the human hepatic lipase (LIPC) gene promoter. J Lipid Res 2006 Jul;47(7):1463-77

Date

04/11/2006

Pubmed ID

16603721

DOI

10.1194/jlr.M600082-JLR200

Scopus ID

2-s2.0-33746103335 (requires institutional sign-in at Scopus site)   39 Citations

Abstract

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 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. PGC-1alpha is capable of stimulating the HNF4alpha-dependent transactivation 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 cotransfection 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 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.

Author List

Rufibach LE, Duncan SA, Battle M, Deeb SS

MESH terms used to index this publication - Major topics in bold

Animals
Base Sequence
Binding Sites
COS Cells
COUP Transcription Factor II
Cell Line
DNA
Gene Expression Regulation, Enzymologic
Heat-Shock Proteins
Hepatocyte Nuclear Factor 1-alpha
Hepatocyte Nuclear Factor 4
Humans
Lipase
Liver
Mice
Mice, Knockout
Models, Biological
Molecular Sequence Data
Mutagenesis, Site-Directed
Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
Promoter Regions, Genetic
Receptors, Cytoplasmic and Nuclear
Recombinant Proteins
Transcription Factors
Transcriptional Activation
Transfection