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Regulation of hepatic mitochondrial metabolism in response to a high fat diet: a longitudinal study in rats

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Abstract

Mitochondrial dysfunctions have been detected in non-alcoholic steatohepatitis, but less information exists regarding adaptation of mitochondrial function during the initiation of hepatic steatosis. This study aimed to determine in rat liver the sequence of mitochondrial and metabolic adaptations occurring during the first 8 weeks of a moderate high fat diet (HFD). Sprague–Dawley rats were fed a HFD during 2, 4, and 8 weeks. Mitochondrial oxygen consumption, respiratory chain complexes activity, and oxidative phosphorylation efficiency were assessed in isolated liver mitochondria. Gene expression related to fat metabolism and mitochondrial biogenesis were determined. Results were compared to data collected in a group of rats sacrificed before starting the HFD feeding. After 2 and 4 weeks of HFD, there was a development of fatty liver and a concomitant increase the expression of mitochondrial glycerol-3-phosphate acyltransferase (mtGPAT) and peroxisome proliferator-activated receptor γ. Higher serum β-hydroxybutyrate levels and enhanced hepatic pyruvate dehydrogenase kinase 4 expression suggested increased fatty acid oxidation. However, mitochondrial respiration and respiratory chain activity were normal. After 8 weeks of HFD, lower accumulation of liver triglycerides was associated with reduced expression of mtGPAT. At this time, oxygen consumption with palmitoyl-l-carnitine was decreased whereas oxidative phosphorylation efficiency (ATP/O) with succinate was enhanced. Hepatic levels of mtDNA were unchanged whatever the time points. This longitudinal study in rats fed a HFD showed that hepatic lipid homeostasis and mitochondrial function can adapt to face the increase in fatty acid availability.

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Abbreviations

HFD:

High fat diet

RCR:

Respiratory control ratio

CS:

Citrate synthase

TG:

Triglyceride

mtDNA:

Mitochondrial DNA

HPRT:

Hypoxanthine guanine phosphoribosyl transferase

PGC1α and β:

Peroxisome proliferator-activated receptor γ coactivator 1 α and β

TFAM:

Mitochondrial transcription factor A

NRF1:

Nuclear respiratory factor 1

ERRα:

Estrogen-related receptor α

SCD1:

Stearoyl-coenzyme A desaturase 1

mtGPAT:

Mitochondrial glycerol-3-phosphate acyltransferase

PPARα and γ:

Peroxisome proliferator-activated receptor α and γ

CPT1:

Carnitine palmitoyltransferase 1

PDK4:

Pyruvate dehydrogenase kinase 4

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Acknowledgments

Melissa Flamment was supported by a grant from "Conseil Régional Pays de la Loire/Inserm". The authors thank Jerome Roux, Pierre Legras, and Laurent Buffet for animal care.

Authors’ contributions

Mélissa Flamment conducted all the study, with the help of Naig Gueguen and Gilles Simard for mitochondrial respiration. Jennifer Rieusset and Hubert Vidal did the gene expression quantifications. Yves Malthiery, Bernard Fromenty, and Pierre-Henri Ducluzeau were involved in the design and the manuscript writing.

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Authors and Affiliations

  1. INSERM, U694, Université de Angers, 4 rue Larrey, Angers, 49033, France

    Mélissa Flamment, Gilles Simard, Yves Malthièry & Pierre-Henri Ducluzeau

  2. INSERM 870, Université Lyon 1, Hospices Civils de Lyon, Lyon, France

    Jennifer Rieusset & Hubert Vidal

  3. INSERM 991, Université Rennes 1, Rennes, France

    Bernard Fromenty

Authors
  1. Mélissa Flamment
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  2. Jennifer Rieusset
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  3. Hubert Vidal
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  4. Gilles Simard
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  5. Yves Malthièry
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  6. Bernard Fromenty
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  7. Pierre-Henri Ducluzeau
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Correspondence to Pierre-Henri Ducluzeau.

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Flamment, M., Rieusset, J., Vidal, H. et al. Regulation of hepatic mitochondrial metabolism in response to a high fat diet: a longitudinal study in rats. J Physiol Biochem 68, 335–344 (2012). https://doi.org/10.1007/s13105-012-0145-3

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  • DOI: https://doi.org/10.1007/s13105-012-0145-3

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