The full induction of human apoprotein A-I gene expression by the experimental nephrotic syndrome in transgenic mice depends on cis-acting elements in the proximal 256 base-pair promoter region and the trans-acting factor early growth response factor 1

Mohamed Zaiou, Neal Azrolan, Tony Hayek, Hongxing Wang, Lin Wu, Mehrdad Haghpassand, Borut Cizman, Michael P. Madaio, Jeffrey Milbrandt, Julian B. Marsh, Jan L. Breslow, Edward A. Fisher

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Abstract

To identify molecular factors regulating apo A-I production in vivo, we induced in transgenic mice the experimental nephrotic syndrome, which results in elevated levels of HDL cholesterol (HDL-C), plasma apo A-I, and hepatic apo A-I mRNA. Human (h) apo A-I transgenic mice with different length 5' flanking sequences (5.5 or 0.256 kb, the core promoter for hepatic-specific basal expression) were injected with nephrotoxic (NTS) or control serum. With nephrosis, there were comparable (greater than two fold) increases in both lines of HDL-C, h-apo A-I, and hepatic h-apo A-I mRNA, suggesting that cis- acting elements regulating induced apo A-I gene expression were within its core promoter. Hepatic nuclear extracts from control and nephrotic mice footprinted the core promoter similarly, implying that the same elements regulated basal and induced expression. Hepatic mRNA levels for hepatocyte nuclear factor (HNF) 4 and early growth response factor (EGR) 1, trans- acting factors that bind to the core promoter, were measured: HNF4 mRNA was not affected, but that of EGR-1 was elevated approximately fivefold in the nephrotic group. EGR-1 knockout (EGR1-KO) mice and highest in nephrotic mice expressing EGR-1. Although in EGR1-KO mice HDL-C, apo A-I, and apo A-I mRNA levels also increased after NTS injection, they were approximately half of those in the nephrotic EGR-1-expressing mice. We conclude that in this model, basal and induced apo A-I gene expression in vivo are regulated by the trans- acting factor EGR-1 and require the same cis-acting elements in the core promoter.

Original languageEnglish (US)
Pages (from-to)1699-1707
Number of pages9
JournalJournal of Clinical Investigation
Volume101
Issue number8
DOIs
StatePublished - Apr 15 1998

Fingerprint

Apoproteins
Trans-Activators
Apolipoprotein A-I
Nephrotic Syndrome
Genetic Promoter Regions
Base Pairing
Transgenic Mice
Intercellular Signaling Peptides and Proteins
Gene Expression
Messenger RNA
Liver
HDL Cholesterol
Knockout Mice
Hepatocyte Nuclear Factor 4
Nephrosis
5' Flanking Region
Injections

Keywords

  • Gene expression
  • High density lipoprotein
  • Kidney
  • Liver
  • Transcription

ASJC Scopus subject areas

  • Medicine(all)

Cite this

The full induction of human apoprotein A-I gene expression by the experimental nephrotic syndrome in transgenic mice depends on cis-acting elements in the proximal 256 base-pair promoter region and the trans-acting factor early growth response factor 1. / Zaiou, Mohamed; Azrolan, Neal; Hayek, Tony; Wang, Hongxing; Wu, Lin; Haghpassand, Mehrdad; Cizman, Borut; Madaio, Michael P.; Milbrandt, Jeffrey; Marsh, Julian B.; Breslow, Jan L.; Fisher, Edward A.

In: Journal of Clinical Investigation, Vol. 101, No. 8, 15.04.1998, p. 1699-1707.

Research output: Contribution to journalArticle

Zaiou, Mohamed ; Azrolan, Neal ; Hayek, Tony ; Wang, Hongxing ; Wu, Lin ; Haghpassand, Mehrdad ; Cizman, Borut ; Madaio, Michael P. ; Milbrandt, Jeffrey ; Marsh, Julian B. ; Breslow, Jan L. ; Fisher, Edward A. / The full induction of human apoprotein A-I gene expression by the experimental nephrotic syndrome in transgenic mice depends on cis-acting elements in the proximal 256 base-pair promoter region and the trans-acting factor early growth response factor 1. In: Journal of Clinical Investigation. 1998 ; Vol. 101, No. 8. pp. 1699-1707.
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abstract = "To identify molecular factors regulating apo A-I production in vivo, we induced in transgenic mice the experimental nephrotic syndrome, which results in elevated levels of HDL cholesterol (HDL-C), plasma apo A-I, and hepatic apo A-I mRNA. Human (h) apo A-I transgenic mice with different length 5' flanking sequences (5.5 or 0.256 kb, the core promoter for hepatic-specific basal expression) were injected with nephrotoxic (NTS) or control serum. With nephrosis, there were comparable (greater than two fold) increases in both lines of HDL-C, h-apo A-I, and hepatic h-apo A-I mRNA, suggesting that cis- acting elements regulating induced apo A-I gene expression were within its core promoter. Hepatic nuclear extracts from control and nephrotic mice footprinted the core promoter similarly, implying that the same elements regulated basal and induced expression. Hepatic mRNA levels for hepatocyte nuclear factor (HNF) 4 and early growth response factor (EGR) 1, trans- acting factors that bind to the core promoter, were measured: HNF4 mRNA was not affected, but that of EGR-1 was elevated approximately fivefold in the nephrotic group. EGR-1 knockout (EGR1-KO) mice and highest in nephrotic mice expressing EGR-1. Although in EGR1-KO mice HDL-C, apo A-I, and apo A-I mRNA levels also increased after NTS injection, they were approximately half of those in the nephrotic EGR-1-expressing mice. We conclude that in this model, basal and induced apo A-I gene expression in vivo are regulated by the trans- acting factor EGR-1 and require the same cis-acting elements in the core promoter.",
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AU - Zaiou, Mohamed

AU - Azrolan, Neal

AU - Hayek, Tony

AU - Wang, Hongxing

AU - Wu, Lin

AU - Haghpassand, Mehrdad

AU - Cizman, Borut

AU - Madaio, Michael P.

AU - Milbrandt, Jeffrey

AU - Marsh, Julian B.

AU - Breslow, Jan L.

AU - Fisher, Edward A.

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N2 - To identify molecular factors regulating apo A-I production in vivo, we induced in transgenic mice the experimental nephrotic syndrome, which results in elevated levels of HDL cholesterol (HDL-C), plasma apo A-I, and hepatic apo A-I mRNA. Human (h) apo A-I transgenic mice with different length 5' flanking sequences (5.5 or 0.256 kb, the core promoter for hepatic-specific basal expression) were injected with nephrotoxic (NTS) or control serum. With nephrosis, there were comparable (greater than two fold) increases in both lines of HDL-C, h-apo A-I, and hepatic h-apo A-I mRNA, suggesting that cis- acting elements regulating induced apo A-I gene expression were within its core promoter. Hepatic nuclear extracts from control and nephrotic mice footprinted the core promoter similarly, implying that the same elements regulated basal and induced expression. Hepatic mRNA levels for hepatocyte nuclear factor (HNF) 4 and early growth response factor (EGR) 1, trans- acting factors that bind to the core promoter, were measured: HNF4 mRNA was not affected, but that of EGR-1 was elevated approximately fivefold in the nephrotic group. EGR-1 knockout (EGR1-KO) mice and highest in nephrotic mice expressing EGR-1. Although in EGR1-KO mice HDL-C, apo A-I, and apo A-I mRNA levels also increased after NTS injection, they were approximately half of those in the nephrotic EGR-1-expressing mice. We conclude that in this model, basal and induced apo A-I gene expression in vivo are regulated by the trans- acting factor EGR-1 and require the same cis-acting elements in the core promoter.

AB - To identify molecular factors regulating apo A-I production in vivo, we induced in transgenic mice the experimental nephrotic syndrome, which results in elevated levels of HDL cholesterol (HDL-C), plasma apo A-I, and hepatic apo A-I mRNA. Human (h) apo A-I transgenic mice with different length 5' flanking sequences (5.5 or 0.256 kb, the core promoter for hepatic-specific basal expression) were injected with nephrotoxic (NTS) or control serum. With nephrosis, there were comparable (greater than two fold) increases in both lines of HDL-C, h-apo A-I, and hepatic h-apo A-I mRNA, suggesting that cis- acting elements regulating induced apo A-I gene expression were within its core promoter. Hepatic nuclear extracts from control and nephrotic mice footprinted the core promoter similarly, implying that the same elements regulated basal and induced expression. Hepatic mRNA levels for hepatocyte nuclear factor (HNF) 4 and early growth response factor (EGR) 1, trans- acting factors that bind to the core promoter, were measured: HNF4 mRNA was not affected, but that of EGR-1 was elevated approximately fivefold in the nephrotic group. EGR-1 knockout (EGR1-KO) mice and highest in nephrotic mice expressing EGR-1. Although in EGR1-KO mice HDL-C, apo A-I, and apo A-I mRNA levels also increased after NTS injection, they were approximately half of those in the nephrotic EGR-1-expressing mice. We conclude that in this model, basal and induced apo A-I gene expression in vivo are regulated by the trans- acting factor EGR-1 and require the same cis-acting elements in the core promoter.

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