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Fatty acid-induced lipotoxicity inhibits choline metabolism independent of ER stress in mouse primary hepatocytes

Conor O’Dwyer, Rebecca Yaworski, Nicholas D. LeBlond, Peyman Ghorbani, Julia R.C. Nunes, Kaitlyn D. Margison, Tyler T.K. Smith, Kaelan Gobeil Odai, Shauna Han, View ORCID ProfileMorgan D. Fullerton
doi: https://doi.org/10.1101/746750
Conor O’Dwyer
1University of Ottawa Faculty of Medicine, Department of Biochemistry, Microbiology and Immunology
2University of Ottawa Centre for Infection, Immunity and Inflammation and Centre for Catalysis Research and Innovation
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Rebecca Yaworski
1University of Ottawa Faculty of Medicine, Department of Biochemistry, Microbiology and Immunology
2University of Ottawa Centre for Infection, Immunity and Inflammation and Centre for Catalysis Research and Innovation
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Nicholas D. LeBlond
1University of Ottawa Faculty of Medicine, Department of Biochemistry, Microbiology and Immunology
2University of Ottawa Centre for Infection, Immunity and Inflammation and Centre for Catalysis Research and Innovation
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Peyman Ghorbani
1University of Ottawa Faculty of Medicine, Department of Biochemistry, Microbiology and Immunology
2University of Ottawa Centre for Infection, Immunity and Inflammation and Centre for Catalysis Research and Innovation
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Julia R.C. Nunes
1University of Ottawa Faculty of Medicine, Department of Biochemistry, Microbiology and Immunology
2University of Ottawa Centre for Infection, Immunity and Inflammation and Centre for Catalysis Research and Innovation
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Kaitlyn D. Margison
1University of Ottawa Faculty of Medicine, Department of Biochemistry, Microbiology and Immunology
2University of Ottawa Centre for Infection, Immunity and Inflammation and Centre for Catalysis Research and Innovation
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Tyler T.K. Smith
1University of Ottawa Faculty of Medicine, Department of Biochemistry, Microbiology and Immunology
2University of Ottawa Centre for Infection, Immunity and Inflammation and Centre for Catalysis Research and Innovation
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Kaelan Gobeil Odai
1University of Ottawa Faculty of Medicine, Department of Biochemistry, Microbiology and Immunology
2University of Ottawa Centre for Infection, Immunity and Inflammation and Centre for Catalysis Research and Innovation
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Shauna Han
1University of Ottawa Faculty of Medicine, Department of Biochemistry, Microbiology and Immunology
2University of Ottawa Centre for Infection, Immunity and Inflammation and Centre for Catalysis Research and Innovation
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Morgan D. Fullerton
1University of Ottawa Faculty of Medicine, Department of Biochemistry, Microbiology and Immunology
2University of Ottawa Centre for Infection, Immunity and Inflammation and Centre for Catalysis Research and Innovation
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  • ORCID record for Morgan D. Fullerton
  • For correspondence: morgan.fullerton@uottawa.ca
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ABSTRACT

Choline is an essential nutrient that is critical component of the membrane phospholipid phosphatidylcholine (PC), the neurotransmitter acetylcholine and the methylation pathway. In the liver specifically, PC is the major membrane constituent and can be synthesized by the CDP-choline or the phosphatidylethanolamine (PE) N-methyltransferase (PEMT) pathway. With the continuing global rise in the rates of obesity and non-alcoholic fatty liver disease, we sought to explore how excess fatty acids (FA), typical of an obesity and hepatic steatosis, affect choline uptake and metabolism in primary hepatocytes. Our results demonstrate that hepatocytes chronically treated with palmitate, but not oleate or a mixture, had decreased choline uptake, which was associated with lower choline incorporation into PC and lower expression of choline transport proteins. Interestingly, a reduction in the rate of degradation spared PC levels in response to palmitate when compared to control. PE synthesis was slightly diminished; however, no compensatory changes in the PEMT pathway were observed. We next hypothesized that ER stress may be a potential mechanism by which palmitate treatment diminished choline. However, when we exposed primary hepatocytes to the common ER stress inducing compound tunicamycin, choline uptake, contrary to our expectation was augmented, concomitant with the transcript expression of choline transporters. Moreover, tunicamycin-induced ER stress divorced the observed increase in choline uptake from CDP-choline pathway flux since ER stress significantly diminished the incorporation and total PC content, similar to PE. Conclusion: Therefore, our results suggest that the altered FA milieu seen in obesity and fatty liver disease progression may adversely affect choline metabolism, but that compensatory mechanisms work to maintain phospholipid homeostasis.

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  • Abbreviations

    PC
    Phosphatidylcholine
    PE
    Phosphatidylethanolamine
    FA
    Fatty acids
    CDP-Choline
    Cytidine diphosphate-choline
    CTL1/2
    Choline transporter-like protein 1/2
    Slc44a1/2
    Solute carrier 44a1 (gene encoding CTL1/2)
    CHKα
    Choline kinase alpha
    CCT
    Phosphocholine cytidylyltransferase (protein)
    Pcyt1a
    Phosphocholine cytidylyltransferase (gene)
    Pcyt2
    Phosphoethanolamine cytidylyltransferase (gene)
    CEPT
    Choline/ethanolamine phosphotransferase
    PEMT
    Phosphatidylethanolamine-N methyltransferase
    WME
    William’s media E
    KRH
    Krebs-Ringer-HEPES
    VLDL
    Very low-density lipoprotein
    SFA
    Saturated fatty acids
    MUFA
    Monounsaturated fatty acids
  • Copyright 
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    Posted August 25, 2019.
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    Fatty acid-induced lipotoxicity inhibits choline metabolism independent of ER stress in mouse primary hepatocytes
    Conor O’Dwyer, Rebecca Yaworski, Nicholas D. LeBlond, Peyman Ghorbani, Julia R.C. Nunes, Kaitlyn D. Margison, Tyler T.K. Smith, Kaelan Gobeil Odai, Shauna Han, Morgan D. Fullerton
    bioRxiv 746750; doi: https://doi.org/10.1101/746750
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    Fatty acid-induced lipotoxicity inhibits choline metabolism independent of ER stress in mouse primary hepatocytes
    Conor O’Dwyer, Rebecca Yaworski, Nicholas D. LeBlond, Peyman Ghorbani, Julia R.C. Nunes, Kaitlyn D. Margison, Tyler T.K. Smith, Kaelan Gobeil Odai, Shauna Han, Morgan D. Fullerton
    bioRxiv 746750; doi: https://doi.org/10.1101/746750

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