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
(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)
Please use this url to cite or link to this publication:
https://lup.lub.lu.se/record/892478
- author
- Gerbod-Giannone, MC ; del Castillo-Olivares, A ; Janciauskiene, Sabina LU ; Gil, G and Hylemon, PB
- organization
- publishing date
- 2002
- type
- Contribution to journal
- publication status
- published
- subject
- in
- Journal of Biological Chemistry
- volume
- 277
- issue
- 45
- pages
- 42973 - 42980
- publisher
- American Society for Biochemistry and Molecular Biology
- 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
- 2016-04-01 12:12:48
- date last changed
- 2022-03-28 21:51:19
@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 = {{American Society for Biochemistry and Molecular Biology}},
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}},
doi = {{10.1074/jbc.M205089200}},
volume = {{277}},
year = {{2002}},
}