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Suppression of cholesterol 7 alpha-hydroxylase transcription and bile acid synthesis by an alpha(1)-antitrypsin peptide via interaction with alpha(1)-fetoprotein transcription factor

Gerbod-Giannone, MC; del Castillo-Olivares, A; Janciauskiene, Sabina LU ; Gil, G and Hylemon, PB (2002) In Journal of Biological Chemistry 277(45). p.42973-42980
Abstract
alpha(1)-Antitrypsin (alpha(1)-AT) is a serum protease inhibitor that is synthesized mainly in the liver, and its rate of synthesis markedly increases in response to inflammation. This increase in alpha(1)-AT synthesis results in an increase in peptides, like its carboxyl-terminal C-36 peptide (C-36), resulting from alpha(1)-AT cleavage by proteases. Atherosclerosis is a form of chronic inflammation, and one of the risk factors is elevated plasma cholesterol levels. Because of the correlation between atherosclerosis, plasma cholesterol content, inflammation, and alpha(1)-AT rate of synthesis, we investigated the effect of the C-36 serpin peptide on hepatic bile acid biosynthesis. We discovered that C-36 is a powerful and specific... (More)
alpha(1)-Antitrypsin (alpha(1)-AT) is a serum protease inhibitor that is synthesized mainly in the liver, and its rate of synthesis markedly increases in response to inflammation. This increase in alpha(1)-AT synthesis results in an increase in peptides, like its carboxyl-terminal C-36 peptide (C-36), resulting from alpha(1)-AT cleavage by proteases. Atherosclerosis is a form of chronic inflammation, and one of the risk factors is elevated plasma cholesterol levels. Because of the correlation between atherosclerosis, plasma cholesterol content, inflammation, and alpha(1)-AT rate of synthesis, we investigated the effect of the C-36 serpin peptide on hepatic bile acid biosynthesis. We discovered that C-36 is a powerful and specific transcriptional down-regulator of bile acid synthesis in primary rat hepatocytes, through inhibition of the cholesterol 7alpha-hydroxylase/CYP7A1 (7alpha-hydroxylase) promoter. Mice injected with the C-36 peptide also showed a decrease in 7alpha-hydroxylase mRNA. A mutated but very similar peptide did not have any effect on 7alpha-hydroxylase mRNA or its promoter. The sterol 12alpha-hydroxylase/ CYP8B1 (12alpha-hydroxylase) promoter is also down-regulated by the C-36 peptide in HepG2 cells but not by the mutated peptide. The DNA element involved in the C-36-mediated regulation of 7alpha- and 12a-hydroxylase promoters mapped to the alpha(1)-fetoprotein transcription factor (FTF) site in both promoters. The C-36 peptide prevented binding of FTF to its target DNA recognition site by direct interaction with FTF. We hypothesize that the C-36 peptide specifically interacts with FTF and induces a conformational change that results in loss of its DNA binding ability, which results in suppression of 7alpha- and 12alpha-hydroxylase transcription. These results suggest that peptides derived from specific serum proteins may alter hepatic gene expression in a highly specific manner. (Less)
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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Journal of Biological Chemistry
volume
277
issue
45
pages
42973 - 42980
publisher
ASBMB
external identifiers
  • pmid:11711533
  • wos:000179081200072
  • scopus:0037044581
ISSN
1083-351X
DOI
10.1074/jbc.M205089200
language
English
LU publication?
yes
id
f7a712ec-fcc4-4fd0-a9a5-f0982871269e (old id 892478)
date added to LUP
2008-01-22 09:13:50
date last changed
2017-11-12 03:27:14
@article{f7a712ec-fcc4-4fd0-a9a5-f0982871269e,
  abstract     = {alpha(1)-Antitrypsin (alpha(1)-AT) is a serum protease inhibitor that is synthesized mainly in the liver, and its rate of synthesis markedly increases in response to inflammation. This increase in alpha(1)-AT synthesis results in an increase in peptides, like its carboxyl-terminal C-36 peptide (C-36), resulting from alpha(1)-AT cleavage by proteases. Atherosclerosis is a form of chronic inflammation, and one of the risk factors is elevated plasma cholesterol levels. Because of the correlation between atherosclerosis, plasma cholesterol content, inflammation, and alpha(1)-AT rate of synthesis, we investigated the effect of the C-36 serpin peptide on hepatic bile acid biosynthesis. We discovered that C-36 is a powerful and specific transcriptional down-regulator of bile acid synthesis in primary rat hepatocytes, through inhibition of the cholesterol 7alpha-hydroxylase/CYP7A1 (7alpha-hydroxylase) promoter. Mice injected with the C-36 peptide also showed a decrease in 7alpha-hydroxylase mRNA. A mutated but very similar peptide did not have any effect on 7alpha-hydroxylase mRNA or its promoter. The sterol 12alpha-hydroxylase/ CYP8B1 (12alpha-hydroxylase) promoter is also down-regulated by the C-36 peptide in HepG2 cells but not by the mutated peptide. The DNA element involved in the C-36-mediated regulation of 7alpha- and 12a-hydroxylase promoters mapped to the alpha(1)-fetoprotein transcription factor (FTF) site in both promoters. The C-36 peptide prevented binding of FTF to its target DNA recognition site by direct interaction with FTF. We hypothesize that the C-36 peptide specifically interacts with FTF and induces a conformational change that results in loss of its DNA binding ability, which results in suppression of 7alpha- and 12alpha-hydroxylase transcription. These results suggest that peptides derived from specific serum proteins may alter hepatic gene expression in a highly specific manner.},
  author       = {Gerbod-Giannone, MC and del Castillo-Olivares, A and Janciauskiene, Sabina and Gil, G and Hylemon, PB},
  issn         = {1083-351X},
  language     = {eng},
  number       = {45},
  pages        = {42973--42980},
  publisher    = {ASBMB},
  series       = {Journal of Biological Chemistry},
  title        = {Suppression of cholesterol 7 alpha-hydroxylase transcription and bile acid synthesis by an alpha(1)-antitrypsin peptide via interaction with alpha(1)-fetoprotein transcription factor},
  url          = {http://dx.doi.org/10.1074/jbc.M205089200},
  volume       = {277},
  year         = {2002},
}