Blood-derived lysophospholipid sustains hepatic phospholipids and fat storage necessary for hepatoprotection in overnutrition
The liver has a high demand for phosphatidylcholine (PC), particularly in overnutrition, where reduced phospholipid levels have been implicated in the development of nonalcoholic fatty liver disease (NAFLD). Whether other pathways exist in addition to de novo PC synthesis that contribute to hepatic...
| Main Authors: | , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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American Society for Clinical Investigation
2023-09-01
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| Series: | The Journal of Clinical Investigation |
| Subjects: | |
| Online Access: | https://doi.org/10.1172/JCI171267 |
| _version_ | 1797634433869676544 |
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| author | Cheen Fei Chin Dwight L.A. Galam Liang Gao Bryan C. Tan Bernice H. Wong Geok-Lin Chua Randy Y.J. Loke Yen Ching Lim Markus R. Wenk Miao-Shan Lim Wei-Qiang Leow George B.B. Goh Federico Torta David L. Silver |
| author_facet | Cheen Fei Chin Dwight L.A. Galam Liang Gao Bryan C. Tan Bernice H. Wong Geok-Lin Chua Randy Y.J. Loke Yen Ching Lim Markus R. Wenk Miao-Shan Lim Wei-Qiang Leow George B.B. Goh Federico Torta David L. Silver |
| author_sort | Cheen Fei Chin |
| collection | DOAJ |
| description | The liver has a high demand for phosphatidylcholine (PC), particularly in overnutrition, where reduced phospholipid levels have been implicated in the development of nonalcoholic fatty liver disease (NAFLD). Whether other pathways exist in addition to de novo PC synthesis that contribute to hepatic PC pools remains unknown. Here, we identified the lysophosphatidylcholine (LPC) transporter major facilitator superfamily domain containing 2A (Mfsd2a) as critical for maintaining hepatic phospholipid pools. Hepatic Mfsd2a expression was induced in patients having NAFLD and in mice in response to dietary fat via glucocorticoid receptor action. Mfsd2a liver-specific deficiency in mice (L2aKO) led to a robust nonalcoholic steatohepatitis–like (NASH-like) phenotype within just 2 weeks of dietary fat challenge associated with reduced hepatic phospholipids containing linoleic acid. Reducing dietary choline intake in L2aKO mice exacerbated liver pathology and deficiency of liver phospholipids containing polyunsaturated fatty acids (PUFAs). Treating hepatocytes with LPCs containing oleate and linoleate, two abundant blood-derived LPCs, specifically induced lipid droplet biogenesis and contributed to phospholipid pools, while LPC containing the omega-3 fatty acid docosahexaenoic acid (DHA) promoted lipid droplet formation and suppressed lipogenesis. This study revealed that PUFA-containing LPCs drive hepatic lipid droplet formation, suppress lipogenesis, and sustain hepatic phospholipid pools — processes that are critical for protecting the liver from excess dietary fat. |
| first_indexed | 2024-03-11T12:07:41Z |
| format | Article |
| id | doaj.art-65986795ef3e486290872e1e79aa32e1 |
| institution | Directory Open Access Journal |
| issn | 1558-8238 |
| language | English |
| last_indexed | 2024-03-11T12:07:41Z |
| publishDate | 2023-09-01 |
| publisher | American Society for Clinical Investigation |
| record_format | Article |
| series | The Journal of Clinical Investigation |
| spelling | doaj.art-65986795ef3e486290872e1e79aa32e12023-11-07T16:20:46ZengAmerican Society for Clinical InvestigationThe Journal of Clinical Investigation1558-82382023-09-0113317Blood-derived lysophospholipid sustains hepatic phospholipids and fat storage necessary for hepatoprotection in overnutritionCheen Fei ChinDwight L.A. GalamLiang GaoBryan C. TanBernice H. WongGeok-Lin ChuaRandy Y.J. LokeYen Ching LimMarkus R. WenkMiao-Shan LimWei-Qiang LeowGeorge B.B. GohFederico TortaDavid L. SilverThe liver has a high demand for phosphatidylcholine (PC), particularly in overnutrition, where reduced phospholipid levels have been implicated in the development of nonalcoholic fatty liver disease (NAFLD). Whether other pathways exist in addition to de novo PC synthesis that contribute to hepatic PC pools remains unknown. Here, we identified the lysophosphatidylcholine (LPC) transporter major facilitator superfamily domain containing 2A (Mfsd2a) as critical for maintaining hepatic phospholipid pools. Hepatic Mfsd2a expression was induced in patients having NAFLD and in mice in response to dietary fat via glucocorticoid receptor action. Mfsd2a liver-specific deficiency in mice (L2aKO) led to a robust nonalcoholic steatohepatitis–like (NASH-like) phenotype within just 2 weeks of dietary fat challenge associated with reduced hepatic phospholipids containing linoleic acid. Reducing dietary choline intake in L2aKO mice exacerbated liver pathology and deficiency of liver phospholipids containing polyunsaturated fatty acids (PUFAs). Treating hepatocytes with LPCs containing oleate and linoleate, two abundant blood-derived LPCs, specifically induced lipid droplet biogenesis and contributed to phospholipid pools, while LPC containing the omega-3 fatty acid docosahexaenoic acid (DHA) promoted lipid droplet formation and suppressed lipogenesis. This study revealed that PUFA-containing LPCs drive hepatic lipid droplet formation, suppress lipogenesis, and sustain hepatic phospholipid pools — processes that are critical for protecting the liver from excess dietary fat.https://doi.org/10.1172/JCI171267HepatologyMetabolism |
| spellingShingle | Cheen Fei Chin Dwight L.A. Galam Liang Gao Bryan C. Tan Bernice H. Wong Geok-Lin Chua Randy Y.J. Loke Yen Ching Lim Markus R. Wenk Miao-Shan Lim Wei-Qiang Leow George B.B. Goh Federico Torta David L. Silver Blood-derived lysophospholipid sustains hepatic phospholipids and fat storage necessary for hepatoprotection in overnutrition The Journal of Clinical Investigation Hepatology Metabolism |
| title | Blood-derived lysophospholipid sustains hepatic phospholipids and fat storage necessary for hepatoprotection in overnutrition |
| title_full | Blood-derived lysophospholipid sustains hepatic phospholipids and fat storage necessary for hepatoprotection in overnutrition |
| title_fullStr | Blood-derived lysophospholipid sustains hepatic phospholipids and fat storage necessary for hepatoprotection in overnutrition |
| title_full_unstemmed | Blood-derived lysophospholipid sustains hepatic phospholipids and fat storage necessary for hepatoprotection in overnutrition |
| title_short | Blood-derived lysophospholipid sustains hepatic phospholipids and fat storage necessary for hepatoprotection in overnutrition |
| title_sort | blood derived lysophospholipid sustains hepatic phospholipids and fat storage necessary for hepatoprotection in overnutrition |
| topic | Hepatology Metabolism |
| url | https://doi.org/10.1172/JCI171267 |
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