Cited by 52Lipid metabolism and disordersCholesterol and Lipid MetabolismParaoxonase enzyme and polymorphisms

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

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Rufibach, Laura E., Duncan, Stephen A., Battle, Michele, Deeb, Samir S.·2006·Journal of Lipid Research

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.

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  1. Kinnunen, P. K. 1984. Hepatic endothelial lipase: isolation, some characteristics, and physiological role. In Lipases. B. Borgstrom and H. L. Brockman, editors. Elsevier Scientific Publishers, New York. 307-382.

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Authors
Rufibach, L. E., Duncan, S. A., Battle, M., & Deeb, S. S.
Affiliations
  • University of Washington (US)
  • Medical College of Wisconsin (US)
Corresponding author
Rufibach, Laura E.
Venue
Journal of Lipid Research
Publisher
Elsevier BV
Published
2006-07
Volume
47
Issue
7
Pages
1463-1477
ISSN
0022-2275 (ISSN-L)
OpenAlex
W2165402786
Cited by
52
References
79
Citations by year
2026: 4 · 2025: 1 · 2024: 2 · 2023: 3 · 2022: 6 · 2021: 1 · 2020: 2 · 2019: 3 · 2018: 1 · 2017: 1 · 2016: 2 · 2015: 2 · 2014: 1 · 2013: 3 · 2012: 2
FWCI
3.33
Type
journal article
Language
en
Open access
Locations
  • Journal of Lipid Research (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • National Institutes of Health
  • National Heart, Lung, and Blood Institute (HL 64322, R01HL064322)
  • National Institute of Diabetes and Digestive and Kidney Diseases (DK 55743, F32DK067808, R01DK055743)
Topics
  • Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Lipid metabolism and disorders
  • Health Sciences › Medicine › Surgery › Cholesterol and Lipid Metabolism
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Clinical Biochemistry › Paraoxonase enzyme and polymorphisms
Keywords
hepatic lipase, transcriptional regulation, HNF4α, PGC-1α, HNF1A, lipoprotein metabolism, atherosclerosis, coronary artery disease, hepatic gene expression
MeSH terms
Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha, Animals, Base Sequence, Binding Sites, Cell Line, Chlorocebus aethiops, DNA, Heat-Shock Proteins, Humans, Lipase, Liver, Models, Biological, Molecular Sequence Data, Promoter Regions, Genetic, Recombinant Proteins, Transcription Factors, Transfection, Transcriptional Activation, Gene Expression Regulation, Enzymologic, Mutagenesis, Site-Directed, Receptors, Cytoplasmic and Nuclear, Mice, Knockout, COS Cells, Mice, Hepatocyte Nuclear Factor 1-alpha, Hepatocyte Nuclear Factor 4, COUP Transcription Factor II

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