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Blood-derived lysophospholipid sustains hepatic phospholipids and fat storage necessary for hepatoprotection in overnutrition
Cheen Fei Chin, … , Federico Torta, David L. Silver
Cheen Fei Chin, … , Federico Torta, David L. Silver
Published July 18, 2023
Citation Information: J Clin Invest. 2023;133(17):e171267. https://doi.org/10.1172/JCI171267.
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Research Article Hepatology Metabolism Article has an altmetric score of 113

Blood-derived lysophospholipid sustains hepatic phospholipids and fat storage necessary for hepatoprotection in overnutrition

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Abstract

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.

Authors

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

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Figure 2

Liver-specific Mfsd2a deficiency resulted in development of severe steatohepatitis and fibrosis.

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Liver-specific Mfsd2a deficiency resulted in development of severe steat...
(A) Immunoblot showing the expression of Mfsd2a in 2afl/fl and its absence in L2aKO mouse liver (n = 6 per genotype). β-Actin was used as a loading control. Arrows indicate Mfsd2a, which appears in the liver as 2 distinct molecular weight species due to glycosylation (45). (B) Feeding regimen for mice on NASH diet. (C) Histological analysis was performed on liver sections following 16 weeks of NASH diet feeding using H&E, Sirius red, α-SMA, and galectin-3. Scale bars: 50 μm. (D) Morphometry analysis quantified the percentages of area that were positively stained for each of the indicated markers (2afl/fl, n = 8; L2aKO, n = 11). Data are represented as means ± SEM. *P < 0.05; **P < 0.01, 2-tailed Welch’s t test.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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