Caveolin-1 orchestrates the balance between glucose and lipid-dependent energy metabolism: Implications for liver regeneration

Authors

  • Manuel Alejandro Fernández-Rojo,

    1. Institute for Molecular Bioscience, University of Queensland, Brisbane, Queensland, Australia
    2. Centre for Microscopy and Microanalysis, Brisbane, Queensland, Australia
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  • Christina Restall,

    1. Peter McCallum Cancer Centre, Melbourne, Victoria, Australia
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  • Charles Ferguson,

    1. Institute for Molecular Bioscience, University of Queensland, Brisbane, Queensland, Australia
    2. Centre for Microscopy and Microanalysis, Brisbane, Queensland, Australia
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  • Nick Martel,

    1. Institute for Molecular Bioscience, University of Queensland, Brisbane, Queensland, Australia
    2. Department of Endocrinology and Diabetes, Mater Children's Hospital, South Brisbane, Queensland, Australia
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  • Sally Martin,

    1. Institute for Molecular Bioscience, University of Queensland, Brisbane, Queensland, Australia
    2. Centre for Microscopy and Microanalysis, Brisbane, Queensland, Australia
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  • Marta Bosch,

    1. Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
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  • Adam Kassan,

    1. Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
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  • Gary M. Leong,

    1. Institute for Molecular Bioscience, University of Queensland, Brisbane, Queensland, Australia
    2. Department of Endocrinology and Diabetes, Mater Children's Hospital, South Brisbane, Queensland, Australia
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  • Sheree D. Martin,

    1. Metabolic Research Unit, School of Medicine, Deakin University, Geelong, Victoria, Australia
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  • Sean L. McGee,

    1. Metabolic Research Unit, School of Medicine, Deakin University, Geelong, Victoria, Australia
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  • George E.O. Muscat,

    1. Institute for Molecular Bioscience, University of Queensland, Brisbane, Queensland, Australia
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  • Robin L. Anderson,

    1. Peter McCallum Cancer Centre, Melbourne, Victoria, Australia
    2. Department of Pathology, University of Melbourne, Melbourne, Victoria, Australia
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  • Carlos Enrich,

    1. Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
    2. Departament de Biologia Cellular, Immunologia i Neurociències, Facultat de Medicina, Universitat de Barcelona, Barcelona, Spain
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  • Albert Pol,

    1. Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
    2. Institució Catalana de Recerca i Estudis Avançats (ICREA), Spain
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  • Robert G. Parton

    Corresponding author
    1. Institute for Molecular Bioscience, University of Queensland, Brisbane, Queensland, Australia
    2. Centre for Microscopy and Microanalysis, Brisbane, Queensland, Australia
    • University of Queensland, Institute for Molecular Bioscience, Queensland 4072, Brisbane, Australia
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    • fax: 61-7-3346-2339


  • Potential conflict of interest: Nothing to report.

Abstract

Caveolin-1 (CAV1) is a structural protein of caveolae involved in lipid homeostasis and endocytosis. Using newly generated pure Balb/C CAV1 null (Balb/CCAV1−/−) mice, CAV1−/− mice from Jackson Laboratories (JAXCAV1−/−), and CAV1−/− mice developed in the Kurzchalia Laboratory (KCAV1−/−), we show that under physiological conditions CAV1 expression in mouse tissues is necessary to guarantee an efficient progression of liver regeneration and mouse survival after partial hepatectomy. Absence of CAV1 in mouse tissues is compensated by the development of a carbohydrate-dependent anabolic adaptation. These results were supported by extracellular flux analysis of cellular glycolytic metabolism in CAV1-knockdown AML12 hepatocytes, suggesting cell autonomous effects of CAV1 loss in hepatic glycolysis. Unlike in KCAV1−/− livers, in JAXCAV1−/− livers CAV1 deficiency is compensated by activation of anabolic metabolism (pentose phosphate pathway and lipogenesis) allowing liver regeneration. Administration of 2-deoxy-glucose in JAXCAV1−/− mice indicated that liver regeneration in JAXCAV1−/− mice is strictly dependent on hepatic carbohydrate metabolism. Moreover, with the exception of regenerating JAXCAV1−/− livers, expression of CAV1 in mice is required for efficient hepatic lipid storage during fasting, liver regeneration, and diet-induced steatosis in the three CAV1−/− mouse strains. Furthermore, under these conditions CAV1 accumulates in the lipid droplet fraction in wildtype mouse hepatocytes. Conclusion: Our data demonstrate that lack of CAV1 alters hepatocyte energy metabolism homeostasis under physiological and pathological conditions. (HEPATOLOGY 2011)

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