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 1

Hepatic Mfsd2a is an early response gene and is upregulated with increasing NAFLD severity in patients.

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Hepatic Mfsd2a is an early response gene and is upregulated with increas...
(A) Feeding regimen for NASH diet–induced fatty liver in WT mice. (B) Levels of hepatic Mfsd2a expression in WT mice fed a NASH diet relative to normal chow–fed mice over time (2 weeks, n = 7; 4 weeks, n = 7; 8 weeks, n = 6; 16 weeks, n = 6; normal chow fed controls, n = 4). Mfsd2a mRNA expression was normalized to β-actin. Data are represented as the mean ratio of normalized Mfsd2a relative to Mfsd2a expression in normal chow–fed mice ± SEM. *P < 0.05; **P < 0.01, 1-way ANOVA with Dunnett’s test. (C) Hepatic Mfsd2a expression levels in individuals of normal weight (n = 14), obese individuals (n = 12), and individuals with NAFLD (n = 15) and NASH (n = 16). Normalized Mfsd2a expression was analyzed from RNA-Seq data set GSE126848. Data are expressed as normalized count. *P < 0.05, 1-way ANOVA with Tukey’s test. (D) Immunostaining of Mfsd2a in liver sections from patients without NASH (n = 5) and with NASH (n = 5). Numbers on each image correspond to patient identification numbers in Supplemental Table 1. Scale bars: 50 μm.