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

J Clin Invest. 2023 Sep 1;133(17):e171267. doi: 10.1172/JCI171267.


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.

Keywords: Hepatology; Homeostasis; Metabolism; Mouse models; Transport.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Dietary Fats
  • Liver / metabolism
  • Lysophospholipids / metabolism
  • Mice
  • Non-alcoholic Fatty Liver Disease* / metabolism
  • Overnutrition* / pathology
  • Phosphatidylcholines / metabolism
  • Phospholipids / metabolism


  • Phospholipids
  • Lysophospholipids
  • Phosphatidylcholines
  • Dietary Fats