Know more

Our use of cookies

Cookies are a set of data stored on a user’s device when the user browses a web site. The data is in a file containing an ID number, the name of the server which deposited it and, in some cases, an expiry date. We use cookies to record information about your visit, language of preference, and other parameters on the site in order to optimise your next visit and make the site even more useful to you.

To improve your experience, we use cookies to store certain browsing information and provide secure navigation, and to collect statistics with a view to improve the site’s features. For a complete list of the cookies we use, download “Ghostery”, a free plug-in for browsers which can detect, and, in some cases, block cookies.

Ghostery is available here for free: https://www.ghostery.com/fr/products/

You can also visit the CNIL web site for instructions on how to configure your browser to manage cookie storage on your device.

In the case of third-party advertising cookies, you can also visit the following site: http://www.youronlinechoices.com/fr/controler-ses-cookies/, offered by digital advertising professionals within the European Digital Advertising Alliance (EDAA). From the site, you can deny or accept the cookies used by advertising professionals who are members.

It is also possible to block certain third-party cookies directly via publishers:

Cookie type

Means of blocking

Analytical and performance cookies

Realytics
Google Analytics
Spoteffects
Optimizely

Targeted advertising cookies

DoubleClick
Mediarithmics

The following types of cookies may be used on our websites:

Mandatory cookies

Functional cookies

Social media and advertising cookies

These cookies are needed to ensure the proper functioning of the site and cannot be disabled. They help ensure a secure connection and the basic availability of our website.

These cookies allow us to analyse site use in order to measure and optimise performance. They allow us to store your sign-in information and display the different components of our website in a more coherent way.

These cookies are used by advertising agencies such as Google and by social media sites such as LinkedIn and Facebook. Among other things, they allow pages to be shared on social media, the posting of comments, and the publication (on our site or elsewhere) of ads that reflect your centres of interest.

Our EZPublish content management system (CMS) uses CAS and PHP session cookies and the New Relic cookie for monitoring purposes (IP, response times).

These cookies are deleted at the end of the browsing session (when you log off or close your browser window)

Our EZPublish content management system (CMS) uses the XiTi cookie to measure traffic. Our service provider is AT Internet. This company stores data (IPs, date and time of access, length of the visit and pages viewed) for six months.

Our EZPublish content management system (CMS) does not use this type of cookie.

For more information about the cookies we use, contact INRA’s Data Protection Officer by email at cil-dpo@inra.fr or by post at:

INRA
24, chemin de Borde Rouge –Auzeville – CS52627
31326 Castanet Tolosan CEDEX - France

Dernière mise à jour : Mai 2018

Menu Logo Principal logo Université Clermont Auvergne & associés

Human Nutrition Unit

Zone de texte éditable et éditée et rééditée

Alain Bruhat

Alain Bruhat’s profile
BRUHAT-Alain

Field of Research

Feeding an amino acid-imbalanced diet is a frequent nutritional situation for omnivorous animals living in the wild. This is particularly the case when only a single plant protein source is available, which is most likely partially deficient for one essential amino acid (EAA). Eating a diet partially lacking an EAA results in a decrease in the concentration of the limiting AA in the plasma of the animal that will consequently regulate several physiological functions such as autophagy, food intake…

In addition to nutritional insults, pathological states characterized by a negative nitrogen balance and significant loss of lean body mass, such as cachexia and wasting syndromes can also lead to marked changes in the profiles of free AA in plasma that may affect the activity of the AA-regulated pathways. These pathological states include various forms of trauma (thermal burn, sepsis, fever...) as well as several diseases (chronic renal, cardiac, hepatic and pulmonary diseases, AIDS, cancer…).

These observations led us to decipher the molecular mechanisms involved in the control of physiological functions by amino acids availability.

To answer these questions we address three objectives:

1- Identify the signalling pathways involved in the regulation of gene expression in response to AA starvation in mammals.

2- Identify the physiological functions regulated by the Amino Acid regulated pathway.

3- Identify the role of signalling pathways regulated by amino acids availability in complex nutritional and/or pathological situations.

            Finally, we valorised our basic molecular studies on amino acid control of gene transcription by optimizing a nutritionally inducible system for controlling a therapeutic transgene expression in gene therapy strategies.

 

Research Activity

My research projects aim:

(1) to characterize the transcriptional mechanisms involved in adaptation to EAA deprivation in mammalian cells. We were pioneer in the characterization of the first Amino Acid Response Element (AARE) sequence (Bruhat et al, Mol Cell Biol 2000)

(2) to study these mechanisms at the level of the whole animal in several nutritional and pathophysiological situations.

- Study the role of the eIF2α/ATF4 signaling pathway in the transcriptional regulation of genes involved in apoptotic and autophagic processes: Demonstration that (i) the GCN2-eIF2α-ATF4 pathway regulates the transcription of many genes involved in the maintenance of the autophagic process and (ii) the CHOP transcription factor plays a key role both in the control of autophagy and in cell death in response to EAA deficiency. (B'chir et al, Nucleic Acids Res 2013) (B'chir et al, Cell Signal. 2014)

- Study the role of the eIF2α/ATF4 signaling pathway at the level of the whole animal according to nutritional and pathophysiological situations: (i) Validation of the GCN2-eIF2α-ATF4 pathway functionality in mice; (ii) Demonstration that the GCN2 kinase plays a key role in the induction of TRB3 transcription in mice liver following the consumption of an EAA-deficient diet. (Carraro et al, PLoS One 2010).

- Generation of a novel luciferase mouse line to visualize the spatiotemporal activity of the eIF2/ATF4 pathway: Profiling the eIF2α-ATF4 pathway induction pattern at the tissue and cellular levels. This reporter mouse model represents an important tool for investigating the role of the eIF2α/ATF4 pathway in physiology and diseases (catabolic states, hepatic fibrosis, obesity, diabetes, cancer ...) (Chaveroux et al, Science Signal 2015).

- Development of an inducible gene expression system by nutritional manipulation for gene therapy applications: The system includes an artificial promoter inducible by a deficiency in EAA and an EAA-deficient diet through the GCN2-eIF2α-ATF4 pathway. This system highlights a new concept in the field of gene therapy, that synthetic diets can enable a tight and robust temporal control of therapeutic transgene expression. (Chaveroux et al, Nat Biotechnol 2016)

7 Major publications

Chaveroux C, Bruhat A, Carraro V, Jousse C, Averous J, Maurin AC, Parry L, Mesclon F, Muranishi Y, Cordelier P, Meulle A, Baril P, Do Thi A, Ravassard P, Mallet J, Fafournoux P. Regulating the expression of therapeutic transgenes by controlled intake of dietary essential amino acids. Nat Biotechnol. 2016 Jul;34(7):746-51.

Chaveroux C, Carraro V, Canaple L, Averous J, Maurin AC, Jousse C, Muranishi Y, Parry L, Mesclon F, Gatti E, Mallet J, Ravassard P, Pierre P, Fafournoux P, Bruhat A. In vivo imaging of the spatiotemporal activity of the eIF2α-ATF4 signaling pathway: Insights into stress and related disorders. Science Signal. 2015 Apr 28;8(374):rs5.

B'chir W, Chaveroux C, Carraro V, Averous J, Maurin AC, Jousse C, Muranishi Y, Parry L, Fafournoux P, Bruhat A. Dual role for CHOP in the crosstalk between autophagy and apoptosis to determine cell fate in response to amino acid deprivation. Cell Signal. 2014 Jul;26(7):1385-91.

B'chir W, Maurin AC, Carraro V, Averous J, Jousse C, Muranishi Y, Parry L, Stepien G, Fafournoux P, Bruhat A. The eIF2α/ATF4 pathway is essential for stress-induced autophagy gene expression. Nucleic Acids Res. 2013 Sep;41(16):7683-99.

Carraro V, Maurin AC, Lambert-Langlais S, Averous J, Chaveroux C, Parry L, Jousse C, Ord D, Ord T, Fafournoux P, Bruhat A. Amino acid availability controls TRB3 transcription in liver through the GCN2/eIF2α/ATF4 pathway. PLoS One. 2010 Dec 21;5(12):e15716.

Chérasse Y, Maurin AC, Chaveroux C, Jousse C, Carraro V, Parry L, Deval C, Chambon C, Fafournoux P, Bruhat A. The p300/CBP-associated factor (PCAF) is a cofactor of ATF4 for amino acid-regulated transcription of CHOP. Nucleic Acids Res. 2007;35(17):5954-65.

Bruhat A, Jousse C, Carraro V, Reimold AM, Ferrara M, Fafournoux P. Amino acids control mammalian gene transcription: activating transcription factor 2 is essential for the amino acid responsiveness of the CHOP promoter. Mol Cell Biol. 2000 Oct;20(19):7192-204.