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Gluten worsens non-alcoholic fatty liver disease by affecting lipogenesis and fatty acid oxidation in diet-induced obese apolipoprotein E-deficient mice

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Abstract

Obesity is closely associated with non-alcoholic fatty liver disease (NAFLD), characterized by hepatic fat accumulation and hepatocyte injury. Preclinical studies have shown exacerbated weight gain associated with an obesogenic gluten-containing diet. However, whether gluten affects obesity-induced hepatic lipid accumulation still remains unclear. We hypothesized that gluten intake could affect fatty liver development in high-fat diet (HFD)-induced obese mice. Thus, we aimed to investigate the impact of gluten intake on NAFLD in HFD-induced obese mice. Male apolipoprotein E-deficient (Apoe-/-) mice were fed with a HFD containing (GD) or not (GFD) vital wheat gluten (4.5%) for 10 weeks. Blood and liver were collected for further analysis. We found that gluten exacerbated weight gain, hepatic fat deposition, and hyperglycemia without affecting the serum lipid profile. Livers of the GD group showed a larger area of fibrosis, associated with the expression of collagen and MMP9, and higher expression of apoptosis-related factors, p53, p21, and caspase-3. The expression of lipogenic factors, such as PPARγ and Acc1, was more elevated and factors related to beta-oxidation, such as PPARα and Cpt1, were lower in the GD group compared to the GFD. Further, gluten intake induced a more significant expression of Cd36, suggesting higher uptake of free fatty acids. Finally, we found lower protein expression of PGC1α followed by lower activation of AMPK. Our data show that gluten-containing high-fat diet exacerbated NAFLD by affecting lipogenesis and fatty acid oxidation in obese Apoe-/- mice through a mechanism involving lower activation of AMPK.

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Acknowledgements

The authors wish to thank the laboratory technician Maria Helena Alves Oliveira.

Funding

This study was financed in part by Coordenação de Aperfeiçoamento de Pessoal de Nı́vel Superior, Brazil (CAPES) Finance Code 001 (postdoctoral fellowship).

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Authors and Affiliations

  1. Department of Biochemistry and Immunology, ICB – Federal University of Minas Gerais, Caixa Postal 486, Belo Horizonte, 30161-970, Brazil

    Edenil Costa Aguilar, Weslley Fernandes-Braga, Elandia Aparecida Santos, Paola Caroline Lacerda Leocádio & Jacqueline I. Alvarez-Leite

  2. Department of Pharmacology, Federal University of Minas Gerais, Belo Horizonte, Brazil

    Luciano dos Santos Aggum Capettini & Juliana Maria Navia-Pelaez

  3. Department of General Pathology, Federal University of Minas Gerais, Belo Horizonte, Brazil

    Laura Alejandra Ariza Orellano & Paula Peixoto Campos

  4. Department of Physiology and Biophysics, Federal University of Minas Gerais, Belo Horizonte, Brazil

    Virginia Soares Lemos

  5. Department of Integrated Health Education, Federal University of Espírito Santo, Vitória, Brazil

    Fabíola Lacerda Pires Soares

  6. Precision Immunology Institute at the Icahn School of Medicine at Mount Sinai, New York, NY, USA

    Edenil Costa Aguilar & Weslley Fernandes-Braga

  7. Department of Medicine, University of California San Diego, San Diego, USA

    Juliana Maria Navia-Pelaez

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Contributions

ECA: Conceptualization, project administration, design of the study, methodology, formal analysis, investigation, data curation, and writing-original draft preparation. WFB: Methodology and revised the manuscript critically for intellectual content. EAS: Methodology. PCLL: Methodology and revised the manuscript critically for intellectual content. LSAC: Conceptualization, resources, and design of the study. LAAO: Methodology and interpretation of data. PPC: Resources and data analysis. VSL: Resources and acquisition of data. FLPS: Conceptualization and revised the manuscript critically for intellectual content. JMNP: Conceptualization and methodology. JIAL: Conceptualization, supervision, project administration, design of the study, and reviewing and editing the manuscript.

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Aguilar, E.C., Fernandes-Braga, W., Santos, E.A. et al. Gluten worsens non-alcoholic fatty liver disease by affecting lipogenesis and fatty acid oxidation in diet-induced obese apolipoprotein E-deficient mice. Mol Cell Biochem (2023). https://doi.org/10.1007/s11010-023-04802-3

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