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

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

doi:10.1194/jlr.m600082-jlr200

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.

Highlights

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
We demonstrate that the hepatic lipase gene (LIPC) proximal promoter is regulated by hepatocyte nuclear factor 4a (HNF4a), proliferator-activated receptor g coactivator-1a (PGC-1a), hepatocyte nuclear factor 1a (HNF1a), and A-I regulatory protein-1 (ARP-1) via the DR1, DR4, and HNF1 binding sites but is not regulated by retinoic acid receptor a (RARa) and retinoid X receptor a (RXRa)
Sequence evaluation of the proximal LIPC gene promoter revealed the presence of two inverted direct repeat (DR) elements (Fig. 1A) that conform to the consensus DNA response element half-site 59-RG(G/T)TCA-39 (Fig. 1B)

Summary

Introduction

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. Only a few transcription factor binding sites have been identified in the hepatic lipase gene (LIPC) proximal promoter (Fig. 1A).

Results

Conclusion