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

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

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 3

Mfsd2a is regulated by GR during overnutrition stress.

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Mfsd2a is regulated by GR during overnutrition stress. (A) GRE consensu...
(A) GRE consensus motifs. (B) Chip-Seq profile showing GR occupancy at intron 2 in Dex- or vehicle-injected mice. (C) Luciferase reporter assay defines the GRE in Mfsd2a intron 2. HeLa cells were transfected with the indicated deletions or point mutation constructs of Mfsd2a intron 2 fused upstream of luciferase. Data are expressed as fold change of luciferase activity in 100 nM Dex-treated relative to vehicle-treated control cells, means ± SEM. (D) Immunoblot analysis showing the protein expression of Mfsd2a, indicated by the arrow, in 5 mg/kg Dex-injected (n = 4) or vehicle-injected (n = 4). GAPDH was used as a loading control. (E) Mfsd2a protein expression in GRfl/fl (n = 6) and LGRKO mice (n = 5) fed a normal chow diet at ZT12 (fasted for 12 hours). (F) Mfsd2a mRNA expression in GRfl/fl (n = 6) and LGRKO mice (n = 5) fed a normal chow diet at ZT12 (fasted for 12 hours). (G) Mfsd2a mRNA expression in GRfl/fl and LGRKO mice (n = 7 per genotype) fed a NASH diet for 2 weeks. Data are represented as means ± SEM. **P < 0.001; ***P < 0.01, 2-tailed Welch’s t test.