Regulation of Human Apolipoprotein M Gene Expression by Orphan and Ligand-dependent Nuclear Receptors

Mosialou, Ioanna; Zannis, Vassilis I.; Kardassis, Dimitris

doi:10.1074/jbc.m110.131771

Cited by 36 publications

(34 citation statements)

References 66 publications

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“…Using two different pairs of primers for analysis of HNF4a by RT-qPCR, the basal expression levels of HNF4a mRNA in HepG2 cells were much higher than those of CYP26A1 mRNA (data not shown). Previously, similar kinetic responses have been reported for HNF4a expression in HepG2 cells treated with 9-cis-RA [Hatzis and Talianidis, 2001;Mosialou et al, 2010].…”

Section: Ra Increases the Expression Of Hnf4a In Hepg2 Cellssupporting

confidence: 82%

Hepatocyte Nuclear Factor 4α (HNF4α) in Coordination With Retinoic Acid Receptors Increases all‐trans‐Retinoic Acid‐Dependent CYP26A1 Gene Expression in HepG2 Human Hepatocytes

Zolfaghari

Ross

2014

J of Cellular Biochemistry

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CYP26A1 expression is very highly induced by retinoic acid (RA) in the liver, compared to most other tissues, suggesting that a liver-enriched factor may be required for its physiological transcriptional response. HNF4α is a highly conserved liver-specific/enriched member of nuclear receptor superfamily. In this study, we hypothesized that HNF4α and RARs may cooperate in an RA-dependent manner to induce a high level of CYP26A1 expression in liver cells. Partial inhibition of endogenous HNF4α by siRNA reduced the level of RA-induced CYP26A1 mRNA in HepG2 cells. Cotransfection of HNF4α, with or without RARs, demonstrated RA-dependent activation of a human CYP26A1 promoter-luciferase construct. Analysis of a 2.5-kbp putative CYP26A1 promoter sequence identified five potential HNF4α DNA response elements: H1 located in a proximal region overlapping with an RAR element-1 (RARE1 or R1); H2 and H3 in the distal region, close to RARE2 (R2) and RARE3 (R3); and H4 and H5 in intermediary regions. In EMSA and ChIP analyses HNF4α and RARs binding in the proximal and distal CYP26A1 promoter regions was significantly higher in RA-treated cells. Mutational analysis of the individual HNF4α DNA-response elements identified H1 as the major site for HNF4α binding because mutation of H1 inhibited the promoter activity by ~90%, followed by H2 mutation with less than 40% inhibition. Our results indicate that HNF4α coordinates with RARs in an RA-dependent manner to strongly induce CYP26A1 gene expression in the liver, which may explain the high level of response to RA observed in vivo.

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Section: Ra Increases the Expression Of Hnf4a In Hepg2 Cellssupporting

confidence: 82%

Hepatocyte Nuclear Factor 4α (HNF4α) in Coordination With Retinoic Acid Receptors Increases all‐trans‐Retinoic Acid‐Dependent CYP26A1 Gene Expression in HepG2 Human Hepatocytes

Zolfaghari

Ross

2014

J of Cellular Biochemistry

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“…RXR/TR and RXR/LXR heterodimers bind to a hormone-response element (HRE), which consists of DR-1 at -33 to -21 bp in human apoM gene promoter. Both T3 and 22(R)-OH-cholesterol induce this gene promoter activity [51]. It is of note that the HRE constitutes DR-1, but not DR-4, which is not typical for the competitive binding of the two receptors of TR and LXR.…”

Section: Apolipoprotein Mmentioning

confidence: 99%

Crosstalk of thyroid hormone receptor and liver X receptor in lipid metabolism and beyond [Review]

Hashimoto

Mori

2011

Endocr J

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Abstract. Thyroid hormone receptors (TRs) and liver X receptors (LXRs) are members of the nuclear receptor superfamily. Although LXRs and TRs belong to two distinct receptor subgroups with respect to ligand-binding affinity, the two receptor systems show similarity with respect to molecular mechanism, target genes, and physiological roles. Since both TRs and LXRs play an important role in metabolic regulation, form heterodimers with retinoid X receptors (RXRs), and bind to direct repeat-4 (DR-4) with identical geometry and polarity, crosstalk between these two receptors has been reported, especially on lipid metabolism-related genes. Recently, several types of crosstalk between TRs and LXRs have been identified and crosstalk has also been observed in other physiological systems such as central nervous system rather than lipid metabolism. In this review, recent advances in elucidating the molecular mechanisms of the crosstalk between these two nuclear receptors are discussed, with the aim of finding a perspective on unknown roles of TRs and LXRs.

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“…ApoM is associated with several lipoproteins and is involved in lipid transport (Dahlbäck and Nielsen, ). Its expression is regulated by transcription factors that control hepatic lipid metabolism such as Hepatic Nuclear Factor (HNF)‐1α, Liver Receptor Homolog (LRH)‐1 and Forkhead box A2 (Foxa2) (Wolfrum et al, ; Mosialou et al, ). LEAP2 as antimicrobial peptide is proposed to be part of the vertebrate innate immune system (Krause et al, ).…”

Section: Discussionmentioning

confidence: 99%

Identification of Genes Selectively Regulated in Human Hepatoma Cells by Treatment With Dyslipidemic Sera and PUFAs

Rosa

Caputo

Zirpoli

et al. 2015

Journal Cellular Physiology

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Serum composition is linked to metabolic diseases not only to understand their pathogenesis but also for diagnostic purposes. Quality and quantity of nutritional intake can affect disease risk and serum composition. It is then possible that diet derived serum components directly affect pathogenetic mechanisms. To identify involved factors, we evaluated the effect on gene expression of direct addition of dyslipidemic human serum samples to cultured human hepatoma cells (HepG2). Sera were selected on the basis of cholesterol level, considering this parameter as mostly linked to dietary intake. Cells were treated with 32 sera from hypercholesterolemic and normocholesterolemic subjects to identify differentially regulated mRNAs using DNA microarray analysis. We identified several mRNAs with the highest modulations in cells treated with dyslipidemic sera versus cells treated with normal sera. Since the two serum groups had variable polyunsaturated fatty acids (PUFAs) contents, selected mRNAs were further assessed for their regulation by docosahexaenoic acid (DHA), eicosapentaenoic acid (EPA) and arachidonic acid (AA). Four genes resulted both affected by serum composition and PUFAs: 3-hydroxy-3-methylglutaryl-CoenzymeA synthase 2 (HMGCS2), glutathione S-transferase alpha 1 (GSTA1), liver expressed antimicrobial peptide 2 (LEAP2) and apolipoprotein M (ApoM). HMGCS2 expression appears the most relevant and was also found modulated via transcription factors peroxysome proliferator activated receptor α (PPARα) and forkhead box O1 (FoxO1). Our data indicate that expression levels of the selected mRNAs, primarily of HMGCS2, could represent a reference of nutritional intake, PUFAs effects and dyslipidemic diseases pathogenesis.

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Regulation of Human Apolipoprotein M Gene Expression by Orphan and Ligand-dependent Nuclear Receptors

Cited by 36 publications

References 66 publications

Hepatocyte Nuclear Factor 4α (HNF4α) in Coordination With Retinoic Acid Receptors Increases all‐trans‐Retinoic Acid‐Dependent CYP26A1 Gene Expression in HepG2 Human Hepatocytes

Hepatocyte Nuclear Factor 4α (HNF4α) in Coordination With Retinoic Acid Receptors Increases all‐trans‐Retinoic Acid‐Dependent CYP26A1 Gene Expression in HepG2 Human Hepatocytes

Crosstalk of thyroid hormone receptor and liver X receptor in lipid metabolism and beyond [Review]

Identification of Genes Selectively Regulated in Human Hepatoma Cells by Treatment With Dyslipidemic Sera and PUFAs

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