Hypoxia-induced regulation of the very low density lipoprotein receptor

• The very low density lipoprotein receptor (VLDLr) is highly upregulated during hypoxia in mouse cardiomyocytes and in human and mouse ischemic hearts causing a detrimental lipid accumulation. To know how the gene is regulated is important for future studies. In this study, we have thoroughly mapped the 5 '-flanking region of the mouse VLDLr promoter and show that the hypoxia-mediated increase in VLDLr expression is dependent on Hif-1 alpha, binding to a hypoxia responsive element (HRE) located at -162 to-158 bp 5 ' of translation start. We show that classical HRE sites and the previously described PPAR gamma and Sp1 binding are not involved in the hypoxia-induced regulation of the VLDLr promoter. Using a chromatin immunoprecipitation (ChIP) assay, we show that Hif-1 alpha t specifically binds and activates the mouse VLDLr promoter at the previously described non-classical HRE in HL-1 cells. We also show that the same HRE is present and active in response to hypoxia in human cardiomyocytes, however at a different location (-812 bp from translation start). These results conclude that in the hypoxic hearts of mice and men, the VLDLr gene is regulated by a direct binding of Hif-1 alpha to the VLDLr promoter. (C) 2013 Elsevier Inc. All rights reserved.

Ämnesord

MEDICIN OCH HÄLSOVETENSKAP  -- Klinisk medicin (hsv//swe)

MEDICAL AND HEALTH SCIENCES  -- Clinical Medicine (hsv//eng)

Nyckelord

Very low density lipoprotein receptor

Hypoxia inducible factor 1 alpha

Hypoxia responsive element

TRANSCRIPTIONAL REGULATION

ADIPOCYTE DIFFERENTIATION

BINDING PROTEIN

MESSENGER-RNA

EXPRESSION

GENE

ACTIVATION

PROMOTER

ELEMENTS

ENHANCER

KAHASHI S

1992

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF

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