Hepatic Choline Transport Is Inhibited During Fatty Acid–Induced Lipotoxicity and Obesity
Choline is an essential nutrient and a critical component of the membrane phospholipid phosphatidylcholine (PC), the neurotransmitter acetylcholine, while also contributing to the methylation pathway. In the liver specifically, PC is the major membrane constituent and can be synthesized by the cytid...
| Main Authors: | , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Wolters Kluwer Health/LWW
2020-06-01
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| Series: | Hepatology Communications |
| Online Access: | https://doi.org/10.1002/hep4.1516 |
| _version_ | 1797713826148253696 |
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| author | Conor O’Dwyer Rebecca Yaworski Sakie Katsumura Peyman Ghorbani Kaelan Gobeil Odai Julia R.C. Nunes Nicholas D. LeBlond Sabrin Sanjana Tyler T.K. Smith Shauna Han Kaitlyn D. Margison Tommy Alain Masahiro Morita Morgan D. Fullerton |
| author_facet | Conor O’Dwyer Rebecca Yaworski Sakie Katsumura Peyman Ghorbani Kaelan Gobeil Odai Julia R.C. Nunes Nicholas D. LeBlond Sabrin Sanjana Tyler T.K. Smith Shauna Han Kaitlyn D. Margison Tommy Alain Masahiro Morita Morgan D. Fullerton |
| author_sort | Conor O’Dwyer |
| collection | DOAJ |
| description | Choline is an essential nutrient and a critical component of the membrane phospholipid phosphatidylcholine (PC), the neurotransmitter acetylcholine, while also contributing to the methylation pathway. In the liver specifically, PC is the major membrane constituent and can be synthesized by the cytidine diphosphate–choline or the phosphatidylethanolamine N‐methyltransferase pathway. With the continuing global rise in the rates of obesity and nonalcoholic fatty liver disease, we sought to explore how excess fatty acids on primary hepatocytes and diet‐induced obesity affect choline uptake and metabolism. 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 with control. The effects of palmitate treatment were independent of endoplasmic reticulum stress, which counterintuitively augmented choline transport and transporter expression. In a model of obesity‐induced hepatic steatosis, male mice fed a 60% high‐fat diet for 10 weeks had significantly diminished hepatic choline uptake compared with lean mice fed a control diet. Although the transcript and protein expression of various choline metabolic enzymes fluctuated slightly, we observed reduced protein expression of choline transporter‐like 1 (CTL1) in the liver of mice fed a high‐fat diet. Polysome profile analyses revealed that in livers of obese mice, the CTL1 transcript, despite being more abundant, was translated to a lesser extent compared with lean controls. Finally, human liver cells demonstrated a similar response to palmitate treatment. Conclusion: Our results suggest that the altered fatty acid milieu seen in obesity‐induced fatty liver disease progression may adversely affect choline metabolism, potentially through CTL1, but that compensatory mechanisms work to maintain phospholipid homeostasis. |
| first_indexed | 2024-03-12T07:42:35Z |
| format | Article |
| id | doaj.art-6f21bd4cf0e644f38c1cf1dba71d17bc |
| institution | Directory Open Access Journal |
| issn | 2471-254X |
| language | English |
| last_indexed | 2024-03-12T07:42:35Z |
| publishDate | 2020-06-01 |
| publisher | Wolters Kluwer Health/LWW |
| record_format | Article |
| series | Hepatology Communications |
| spelling | doaj.art-6f21bd4cf0e644f38c1cf1dba71d17bc2023-09-02T21:11:35ZengWolters Kluwer Health/LWWHepatology Communications2471-254X2020-06-014687688910.1002/hep4.1516Hepatic Choline Transport Is Inhibited During Fatty Acid–Induced Lipotoxicity and ObesityConor O’Dwyer0Rebecca Yaworski1Sakie Katsumura2Peyman Ghorbani3Kaelan Gobeil Odai4Julia R.C. Nunes5Nicholas D. LeBlond6Sabrin Sanjana7Tyler T.K. Smith8Shauna Han9Kaitlyn D. Margison10Tommy Alain11Masahiro Morita12Morgan D. Fullerton13Department of Biochemistry, Microbiology and Immunology Faculty of Medicine University of Ottawa Ottawa ON CanadaDepartment of Biochemistry, Microbiology and Immunology Faculty of Medicine University of Ottawa Ottawa ON CanadaDepartment of Molecular Medicine University of Texas Health Science Center at San Antonio San Antonio TXDepartment of Biochemistry, Microbiology and Immunology Faculty of Medicine University of Ottawa Ottawa ON CanadaDepartment of Biochemistry, Microbiology and Immunology Faculty of Medicine University of Ottawa Ottawa ON CanadaDepartment of Biochemistry, Microbiology and Immunology Faculty of Medicine University of Ottawa Ottawa ON CanadaDepartment of Biochemistry, Microbiology and Immunology Faculty of Medicine University of Ottawa Ottawa ON CanadaDepartment of Biochemistry, Microbiology and Immunology Faculty of Medicine University of Ottawa Ottawa ON CanadaDepartment of Biochemistry, Microbiology and Immunology Faculty of Medicine University of Ottawa Ottawa ON CanadaDepartment of Biochemistry, Microbiology and Immunology Faculty of Medicine University of Ottawa Ottawa ON CanadaDepartment of Biochemistry, Microbiology and Immunology Faculty of Medicine University of Ottawa Ottawa ON CanadaDepartment of Biochemistry, Microbiology and Immunology Faculty of Medicine University of Ottawa Ottawa ON CanadaDepartment of Molecular Medicine University of Texas Health Science Center at San Antonio San Antonio TXDepartment of Biochemistry, Microbiology and Immunology Faculty of Medicine University of Ottawa Ottawa ON CanadaCholine is an essential nutrient and a critical component of the membrane phospholipid phosphatidylcholine (PC), the neurotransmitter acetylcholine, while also contributing to the methylation pathway. In the liver specifically, PC is the major membrane constituent and can be synthesized by the cytidine diphosphate–choline or the phosphatidylethanolamine N‐methyltransferase pathway. With the continuing global rise in the rates of obesity and nonalcoholic fatty liver disease, we sought to explore how excess fatty acids on primary hepatocytes and diet‐induced obesity affect choline uptake and metabolism. 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 with control. The effects of palmitate treatment were independent of endoplasmic reticulum stress, which counterintuitively augmented choline transport and transporter expression. In a model of obesity‐induced hepatic steatosis, male mice fed a 60% high‐fat diet for 10 weeks had significantly diminished hepatic choline uptake compared with lean mice fed a control diet. Although the transcript and protein expression of various choline metabolic enzymes fluctuated slightly, we observed reduced protein expression of choline transporter‐like 1 (CTL1) in the liver of mice fed a high‐fat diet. Polysome profile analyses revealed that in livers of obese mice, the CTL1 transcript, despite being more abundant, was translated to a lesser extent compared with lean controls. Finally, human liver cells demonstrated a similar response to palmitate treatment. Conclusion: Our results suggest that the altered fatty acid milieu seen in obesity‐induced fatty liver disease progression may adversely affect choline metabolism, potentially through CTL1, but that compensatory mechanisms work to maintain phospholipid homeostasis.https://doi.org/10.1002/hep4.1516 |
| spellingShingle | Conor O’Dwyer Rebecca Yaworski Sakie Katsumura Peyman Ghorbani Kaelan Gobeil Odai Julia R.C. Nunes Nicholas D. LeBlond Sabrin Sanjana Tyler T.K. Smith Shauna Han Kaitlyn D. Margison Tommy Alain Masahiro Morita Morgan D. Fullerton Hepatic Choline Transport Is Inhibited During Fatty Acid–Induced Lipotoxicity and Obesity Hepatology Communications |
| title | Hepatic Choline Transport Is Inhibited During Fatty Acid–Induced Lipotoxicity and Obesity |
| title_full | Hepatic Choline Transport Is Inhibited During Fatty Acid–Induced Lipotoxicity and Obesity |
| title_fullStr | Hepatic Choline Transport Is Inhibited During Fatty Acid–Induced Lipotoxicity and Obesity |
| title_full_unstemmed | Hepatic Choline Transport Is Inhibited During Fatty Acid–Induced Lipotoxicity and Obesity |
| title_short | Hepatic Choline Transport Is Inhibited During Fatty Acid–Induced Lipotoxicity and Obesity |
| title_sort | hepatic choline transport is inhibited during fatty acid induced lipotoxicity and obesity |
| url | https://doi.org/10.1002/hep4.1516 |
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