Glyceryl triacetate promotes blood-brain barrier recovery after ischemic stroke through lipogenesis-mediated IL-33 in mice

  • J Neuroinflammation. 2023 Nov 15;20(1):264. doi: 10.1186/s12974-023-02942-3.
Haidong Wei  #  1 ,  Luming Zhen  #  1 ,  Shiquan Wang  #  2 ,  Liufei Yang  1 ,  Shuyue Zhang  3 ,  Yuanyuan Zhang  1 ,  Pengyu Jia  1 ,  Tianyue Wang  1 ,  Kui Wang  1 ,  Yan Zhang  1 ,  Lei Ma  1 ,  Jianrui Lv  1 ,  Pengbo Zhang  4
Affiliations
  • 1. Department of Anesthesiology, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710004, Shaanxi, China.
  • 2. Department of Anesthesiology and Perioperative Medicine, Xijing Hospital, The Fourth Military Medical University, Xi'an, 710032, Shaanxi, China.
  • 3. Department of Anesthesiology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, Shaanxi, China.
  • 4. Department of Anesthesiology, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710004, Shaanxi, China. [email protected].
  • # Contributed equally.
PMID: 37968698 DOI: 10.1186/s12974-023-02942-3
Abstract

Background: Lipid metabolism has a crucial role in neural repair in neurodegenerative diseases. We recently revealed that lipogenesis-mediated interleukin-33 (IL-33) upregulation lead to blood-brain barrier (BBB) repair after ischemic stroke. However, manipulating the key enzyme fatty acid synthase (FASN) to enhance lipogenesis was very challenging. Glyceryl triacetate (GTA) was used as a donor of acetate and precursor of acetyl coenzyme A, the key substrate for de novo lipogenesis catalyzed by FASN. Therefore, we hypothesized that GTA would promote lipogenesis the peri-infarct after ischemic stroke and contribute to the BBB repair through IL-33.

Methods: Middle cerebral artery occlusion (MCAO) was performed on C57BL mice and GTA was gavage administrated (4 g/kg) on day 2 and 4 after MCAO. Lipogenesis was evaluated by assessment of the protein level of FASN, lipid droplets, and fatty acid products through liquid chromatography-mass spectrometry in the peri-infarct area on day 3 after MCAO, respectively. BBB permeability was determined by extravasation of Evans blue, IgG and dextran, and levels of tight junction proteins in the peri-infarct area on day 7 after MCAO, respectively. Infarct size and neurological defects were assessed on day 7 after MCAO. Brain atrophy on day 30 and long-term sensorimotor abilities after MCAO were analyzed as well. The inhibitor of FASN, C75 and the virus-delivered FASN shRNA were used to evaluate the role of FASN-driven lipogenesis in GTA-improved BBB repair. Finally, the therapeutic potential of recombinant IL-33 on BBB repair and neurological recovery was evaluated.

Results: We found that treatment with GTA increased the lipogenesis as evidenced by lipid droplets level and lauric acid content, but not the FASN protein level. Treatment with GTA increased the IL-33 level in the peri-infarct area and decreased the BBB permeability after MCAO. However, infarct size and neurological defect score were unchanged on day 7 after MCAO, while the long-term recovery of sensorimotor function and brain atrophy were improved by GTA. Inhibition of lipogenesis using C75 or FASN shRNA reversed the beneficial effect of GTA. Finally, exogenous IL-33 improved BBB repair and long-term functional recovery after stroke.

Conclusion: Collectively, we concluded that treatment with GTA improved the BBB repair and functional recovery after ischemic stroke, probably by the enhancement of lipogenesis and IL-33 expression.

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