FOXO1 represses PPARa-Mediated induction of FGF21 gene expression

Ana Luisa De Sousa-Coelho; Mar Gacias; Brian T. O'Neill; Joana Relat; Wolfgang Link; Diego Haro; Pedro F. Marrero

doi:10.1016/j.bbrc.2023.01.012

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FOXO1 represses PPARa-Mediated induction of FGF21 gene expression

Journal article

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FOXO1 represses PPARa-Mediated induction of FGF21 gene expression

Ana Luisa De Sousa-Coelho, Mar Gacias, Brian T. O'Neill, Joana Relat, Wolfgang Link, Diego Haro and Pedro F. Marrero

Biochemical and biophysical research communications, Vol.644, pp.122-129

02/12/2023

DOI: 10.1016/j.bbrc.2023.01.012

PMID: 36640666

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Abstract

Fibroblast growth factor 21 (FGF21) has emerged as a metabolic regulator that exerts potent anti-diabetic and lipid-lowering effects in animal models of obesity and type 2 diabetes, showing a protective role in fatty liver disease and hepatocellular carcinoma progression. Hepatic expression of FGF21 is regulated by PPARa and is induced by fasting. Ablation of FoxO1 in liver has been shown to increase FGF21 expression in hyperglycemia. To better understand the role of FOXO1 in the regulation of FGF21 expression we have modified HepG2 human hepatoma cells to overexpress FoxO1 and PPARa. Here we show that FoxO1 represses PPARa-mediated FGF21 induction, and that the repression acts on the FGF21 gene promoter without affecting other PPARa target genes. Additionally, we demonstrate that FoxO1 physically interacts with PPARa and that FoxO1/3/4 depletion in skeletal muscle contributes to increased Fgf21 tissue levels. Taken together, these data indicate that FOXO1 is a PPARa-interacting protein that antagonizes PPARa activity on the FGF21 promoter. Because other PPARa target genes remained unaffected, these results suggest a highly specific mechanism implicated in FGF21 regulation. We conclude that FGF21 can be specifically modulated by FOXO1 in a PPARa-dependent manner. (c) 2023 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY-NC license (http://creativecommons.org/licenses/by-nc/4.0/).

Biophysics

Biochemistry & Molecular Biology

Life Sciences & Biomedicine

Science & Technology

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Title: Subtitle: FOXO1 represses PPARa-Mediated induction of FGF21 gene expression
Creators: Ana Luisa De Sousa-Coelho - Algarve Biomedical Center
Mar Gacias - Universitat de Barcelona
Brian T. O'Neill - Fraternal Order of Eagles
Joana Relat - Instituto de Salud Carlos III
Wolfgang Link - Instituto de Investigaciones Biomédicas Sols-Morreale
Diego Haro - Universitat de Barcelona
Pedro F. Marrero - Instituto de Salud Carlos III
Resource Type: Journal article
Publication Details: Biochemical and biophysical research communications, Vol.644, pp.122-129
DOI: 10.1016/j.bbrc.2023.01.012
PMID: 36640666
NLM abbreviation: Biochem Biophys Res Commun
ISSN: 0006-291X
eISSN: 1090-2104
Publisher: Elsevier
Number of pages: 8
Grant note: 2005SGR857 / Ajut de Suport als Grups de Recerca de Catalunya RTI2018-094629-B-I00 / Spanish Ministry of Science, Innovation and Universities; Spanish Government BFU2004-01925; BFU2007-67322/BMC / Ministerio de Educacion y Ciencia; Spanish Government
Language: English
Date published: 02/12/2023
Academic Unit: Endocrinology and Metabolism; Internal Medicine
Record Identifier: 9984375353802771

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