Integrative study of diet-induced mouse models of NAFLD identifies PPARα as a sexually dimorphic drug target

Sarra Smati; Arnaud Polizzi; Anne Fougerat; Sandrine Ellero-Simatos; Yuna Blum; Yannick Lippi; Marion Régnier; Alexia Laroyenne; Marine Huillet; Muhammad Arif; Cheng Zhang; Frederic Lasserre; Alain Marrot; Talal Al Saati; Jing Hong Wan; Caroline Sommer; Claire Naylies; Aurelie Batut; Celine Lukowicz; Tiffany Fougeray; Blandine Tramunt; Patricia Dubot; Lorraine Smith; Justine Bertrand-Michel; Nathalie Hennuyer; Jean Philippe Pradere; Bart Staels; Remy Burcelin; Françoise Lenfant; Jean François Arnal; Thierry Levade; Laurence Gamet-Payrastre; Sandrine Lagarrigue; Nicolas Loiseau; Sophie Lotersztajn; Catherine Postic; Walter Wahli; Christophe Bureau; Maeva Guillaume; Adil Mardinoglu; Alexandra Montagner; Pierre Gourdy; Hervé Guillou

doi:10.1136/gutjnl-2020-323323

Integrative study of diet-induced mouse models of NAFLD identifies PPARα as a sexually dimorphic drug target

Sarra Smati, Arnaud Polizzi, Anne Fougerat, Sandrine Ellero-Simatos, Yuna Blum, Yannick Lippi, Marion Régnier, Alexia Laroyenne, Marine Huillet, Muhammad Arif, Cheng Zhang, Frederic Lasserre, Alain Marrot, Talal Al Saati, Jing Hong Wan, Caroline Sommer, Claire Naylies, Aurelie Batut, Celine Lukowicz, Tiffany FougerayBlandine Tramunt, Patricia Dubot, Lorraine Smith, Justine Bertrand-Michel, Nathalie Hennuyer, Jean Philippe Pradere, Bart Staels, Remy Burcelin, Françoise Lenfant, Jean François Arnal, Thierry Levade, Laurence Gamet-Payrastre, Sandrine Lagarrigue, Nicolas Loiseau, Sophie Lotersztajn, Catherine Postic, Walter Wahli, Christophe Bureau, Maeva Guillaume, Adil Mardinoglu, Alexandra Montagner, Pierre Gourdy^*, Hervé Guillou

^*Corresponding author for this work

Centre for Host Microbiome Interactions

Research output: Contribution to journal › Article › peer-review

32 Citations (Scopus)

Abstract

We evaluated the influence of sex on the pathophysiology of non-alcoholic fatty liver disease (NAFLD). We investigated diet-induced phenotypic responses to define sex-specific regulation between healthy liver and NAFLD to identify influential pathways in different preclinical murine models and their relevance in humans. Different models of diet-induced NAFLD (high-fat diet, choline-deficient high-fat diet, Western diet or Western diet supplemented with fructose and glucose in drinking water) were compared with a control diet in male and female mice. We performed metabolic phenotyping, including plasma biochemistry and liver histology, untargeted large-scale approaches (liver metabolome, lipidome and transcriptome), gene expression profiling and network analysis to identify sex-specific pathways in the mouse liver. The different diets induced sex-specific responses that illustrated an increased susceptibility to NAFLD in male mice. The most severe lipid accumulation and inflammation/fibrosis occurred in males receiving the high-fat diet and Western diet, respectively. Sex-biased hepatic gene signatures were identified for these different dietary challenges. The peroxisome proliferator-activated receptor α (PPARα) co-expression network was identified as sexually dimorphic, and in vivo experiments in mice demonstrated that hepatocyte PPARα determines a sex-specific response to fasting and treatment with pemafibrate, a selective PPARα agonist. Liver molecular signatures in humans also provided evidence of sexually dimorphic gene expression profiles and the sex-specific co-expression network for PPARα. These findings underscore the sex specificity of NAFLD pathophysiology in preclinical studies and identify PPARα as a pivotal, sexually dimorphic, pharmacological target. NCT02390232.

Original language	English
Journal	Gut
DOIs	https://doi.org/10.1136/gutjnl-2020-323323
Publication status	Accepted/In press - 2021

Keywords

gene expression
lipid metabolism
liver metabolism
nonalcoholic steatohepatitis

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Smati, S., Polizzi, A., Fougerat, A., Ellero-Simatos, S., Blum, Y., Lippi, Y., Régnier, M., Laroyenne, A., Huillet, M., Arif, M., Zhang, C., Lasserre, F., Marrot, A., Al Saati, T., Wan, J. H., Sommer, C., Naylies, C., Batut, A., Lukowicz, C., ... Guillou, H. (Accepted/In press). Integrative study of diet-induced mouse models of NAFLD identifies PPARα as a sexually dimorphic drug target. Gut. https://doi.org/10.1136/gutjnl-2020-323323

@article{1eeed1408d2b4d0bb98372ba718fcf75,

title = "Integrative study of diet-induced mouse models of NAFLD identifies PPARα as a sexually dimorphic drug target",

abstract = "We evaluated the influence of sex on the pathophysiology of non-alcoholic fatty liver disease (NAFLD). We investigated diet-induced phenotypic responses to define sex-specific regulation between healthy liver and NAFLD to identify influential pathways in different preclinical murine models and their relevance in humans. Different models of diet-induced NAFLD (high-fat diet, choline-deficient high-fat diet, Western diet or Western diet supplemented with fructose and glucose in drinking water) were compared with a control diet in male and female mice. We performed metabolic phenotyping, including plasma biochemistry and liver histology, untargeted large-scale approaches (liver metabolome, lipidome and transcriptome), gene expression profiling and network analysis to identify sex-specific pathways in the mouse liver. The different diets induced sex-specific responses that illustrated an increased susceptibility to NAFLD in male mice. The most severe lipid accumulation and inflammation/fibrosis occurred in males receiving the high-fat diet and Western diet, respectively. Sex-biased hepatic gene signatures were identified for these different dietary challenges. The peroxisome proliferator-activated receptor α (PPARα) co-expression network was identified as sexually dimorphic, and in vivo experiments in mice demonstrated that hepatocyte PPARα determines a sex-specific response to fasting and treatment with pemafibrate, a selective PPARα agonist. Liver molecular signatures in humans also provided evidence of sexually dimorphic gene expression profiles and the sex-specific co-expression network for PPARα. These findings underscore the sex specificity of NAFLD pathophysiology in preclinical studies and identify PPARα as a pivotal, sexually dimorphic, pharmacological target. NCT02390232.",

keywords = "gene expression, lipid metabolism, liver metabolism, nonalcoholic steatohepatitis",

author = "Sarra Smati and Arnaud Polizzi and Anne Fougerat and Sandrine Ellero-Simatos and Yuna Blum and Yannick Lippi and Marion R{\'e}gnier and Alexia Laroyenne and Marine Huillet and Muhammad Arif and Cheng Zhang and Frederic Lasserre and Alain Marrot and {Al Saati}, Talal and Wan, {Jing Hong} and Caroline Sommer and Claire Naylies and Aurelie Batut and Celine Lukowicz and Tiffany Fougeray and Blandine Tramunt and Patricia Dubot and Lorraine Smith and Justine Bertrand-Michel and Nathalie Hennuyer and Pradere, {Jean Philippe} and Bart Staels and Remy Burcelin and Fran{\c c}oise Lenfant and Arnal, {Jean Fran{\c c}ois} and Thierry Levade and Laurence Gamet-Payrastre and Sandrine Lagarrigue and Nicolas Loiseau and Sophie Lotersztajn and Catherine Postic and Walter Wahli and Christophe Bureau and Maeva Guillaume and Adil Mardinoglu and Alexandra Montagner and Pierre Gourdy and Herv{\'e} Guillou",

note = "Publisher Copyright: {\textcopyright} Author(s) (or their employer(s)) 2021. No commercial re-use. See rights and permissions. Published by BMJ. Copyright: Copyright 2021 Elsevier B.V., All rights reserved.",

year = "2021",

doi = "10.1136/gutjnl-2020-323323",

language = "English",

journal = "Gut",

issn = "0017-5749",

publisher = "BMJ Publishing Group",

}

Smati, S, Polizzi, A, Fougerat, A, Ellero-Simatos, S, Blum, Y, Lippi, Y, Régnier, M, Laroyenne, A, Huillet, M, Arif, M, Zhang, C, Lasserre, F, Marrot, A, Al Saati, T, Wan, JH, Sommer, C, Naylies, C, Batut, A, Lukowicz, C, Fougeray, T, Tramunt, B, Dubot, P, Smith, L, Bertrand-Michel, J, Hennuyer, N, Pradere, JP, Staels, B, Burcelin, R, Lenfant, F, Arnal, JF, Levade, T, Gamet-Payrastre, L, Lagarrigue, S, Loiseau, N, Lotersztajn, S, Postic, C, Wahli, W, Bureau, C, Guillaume, M, Mardinoglu, A, Montagner, A, Gourdy, P & Guillou, H 2021, 'Integrative study of diet-induced mouse models of NAFLD identifies PPARα as a sexually dimorphic drug target', Gut. https://doi.org/10.1136/gutjnl-2020-323323

TY - JOUR

T1 - Integrative study of diet-induced mouse models of NAFLD identifies PPARα as a sexually dimorphic drug target

AU - Smati, Sarra

AU - Polizzi, Arnaud

AU - Fougerat, Anne

AU - Ellero-Simatos, Sandrine

AU - Blum, Yuna

AU - Lippi, Yannick

AU - Régnier, Marion

AU - Laroyenne, Alexia

AU - Huillet, Marine

AU - Arif, Muhammad

AU - Zhang, Cheng

AU - Lasserre, Frederic

AU - Marrot, Alain

AU - Al Saati, Talal

AU - Wan, Jing Hong

AU - Sommer, Caroline

AU - Naylies, Claire

AU - Batut, Aurelie

AU - Lukowicz, Celine

AU - Fougeray, Tiffany

AU - Tramunt, Blandine

AU - Dubot, Patricia

AU - Smith, Lorraine

AU - Bertrand-Michel, Justine

AU - Hennuyer, Nathalie

AU - Pradere, Jean Philippe

AU - Staels, Bart

AU - Burcelin, Remy

AU - Lenfant, Françoise

AU - Arnal, Jean François

AU - Levade, Thierry

AU - Gamet-Payrastre, Laurence

AU - Lagarrigue, Sandrine

AU - Loiseau, Nicolas

AU - Lotersztajn, Sophie

AU - Postic, Catherine

AU - Wahli, Walter

AU - Bureau, Christophe

AU - Guillaume, Maeva

AU - Mardinoglu, Adil

AU - Montagner, Alexandra

AU - Gourdy, Pierre

AU - Guillou, Hervé

PY - 2021

Y1 - 2021

N2 - We evaluated the influence of sex on the pathophysiology of non-alcoholic fatty liver disease (NAFLD). We investigated diet-induced phenotypic responses to define sex-specific regulation between healthy liver and NAFLD to identify influential pathways in different preclinical murine models and their relevance in humans. Different models of diet-induced NAFLD (high-fat diet, choline-deficient high-fat diet, Western diet or Western diet supplemented with fructose and glucose in drinking water) were compared with a control diet in male and female mice. We performed metabolic phenotyping, including plasma biochemistry and liver histology, untargeted large-scale approaches (liver metabolome, lipidome and transcriptome), gene expression profiling and network analysis to identify sex-specific pathways in the mouse liver. The different diets induced sex-specific responses that illustrated an increased susceptibility to NAFLD in male mice. The most severe lipid accumulation and inflammation/fibrosis occurred in males receiving the high-fat diet and Western diet, respectively. Sex-biased hepatic gene signatures were identified for these different dietary challenges. The peroxisome proliferator-activated receptor α (PPARα) co-expression network was identified as sexually dimorphic, and in vivo experiments in mice demonstrated that hepatocyte PPARα determines a sex-specific response to fasting and treatment with pemafibrate, a selective PPARα agonist. Liver molecular signatures in humans also provided evidence of sexually dimorphic gene expression profiles and the sex-specific co-expression network for PPARα. These findings underscore the sex specificity of NAFLD pathophysiology in preclinical studies and identify PPARα as a pivotal, sexually dimorphic, pharmacological target. NCT02390232.

AB - We evaluated the influence of sex on the pathophysiology of non-alcoholic fatty liver disease (NAFLD). We investigated diet-induced phenotypic responses to define sex-specific regulation between healthy liver and NAFLD to identify influential pathways in different preclinical murine models and their relevance in humans. Different models of diet-induced NAFLD (high-fat diet, choline-deficient high-fat diet, Western diet or Western diet supplemented with fructose and glucose in drinking water) were compared with a control diet in male and female mice. We performed metabolic phenotyping, including plasma biochemistry and liver histology, untargeted large-scale approaches (liver metabolome, lipidome and transcriptome), gene expression profiling and network analysis to identify sex-specific pathways in the mouse liver. The different diets induced sex-specific responses that illustrated an increased susceptibility to NAFLD in male mice. The most severe lipid accumulation and inflammation/fibrosis occurred in males receiving the high-fat diet and Western diet, respectively. Sex-biased hepatic gene signatures were identified for these different dietary challenges. The peroxisome proliferator-activated receptor α (PPARα) co-expression network was identified as sexually dimorphic, and in vivo experiments in mice demonstrated that hepatocyte PPARα determines a sex-specific response to fasting and treatment with pemafibrate, a selective PPARα agonist. Liver molecular signatures in humans also provided evidence of sexually dimorphic gene expression profiles and the sex-specific co-expression network for PPARα. These findings underscore the sex specificity of NAFLD pathophysiology in preclinical studies and identify PPARα as a pivotal, sexually dimorphic, pharmacological target. NCT02390232.

KW - gene expression

KW - lipid metabolism

KW - liver metabolism

KW - nonalcoholic steatohepatitis

UR - http://www.scopus.com/inward/record.url?scp=85104886841&partnerID=8YFLogxK

U2 - 10.1136/gutjnl-2020-323323

DO - 10.1136/gutjnl-2020-323323

M3 - Article

AN - SCOPUS:85104886841

SN - 0017-5749

JO - Gut

JF - Gut

ER -

Integrative study of diet-induced mouse models of NAFLD identifies PPARα as a sexually dimorphic drug target

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Keywords

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