2. Academic Validation
  3. TNFα Activates the Liver X Receptor Signaling Pathway and Promotes Cholesterol Efflux from Human Brain Pericytes Independently of ABCA1

TNFα Activates the Liver X Receptor Signaling Pathway and Promotes Cholesterol Efflux from Human Brain Pericytes Independently of ABCA1

  • Int J Mol Sci. 2023 Mar 22;24(6):5992. doi: 10.3390/ijms24065992.
Shiraz Dib 1,  Rodrigo Azevedo Loiola 1,  Emmanuel Sevin 1,  Julien Saint-Pol 1,  Fumitaka Shimizu 2,  Takashi Kanda 2,  Jens Pahnke 3 4 5 6,  Fabien Gosselet 1
Affiliations

Affiliations

  • 1 Blood-Brain Barrier Laboratory (LBHE), UR 2465, University of Artois, F-62300 Lens, France.
  • 2 Department of Neurology and Clinical Neuroscience, Graduate School of Medicine, Yamaguchi University, Ube 755-8505, Japan.
  • 3 Department of Pathology, Section of Neuropathology, Translational Neurodegeneration Research and Neuropathology Lab, University of Oslo, Oslo University Hospital, Sognsvannsveien 20, 0372 Oslo, Norway.
  • 4 Pahnke Lab (Drug Development and Chemical Biology), Lübeck Institute of Experimental Dermatology (LIED), University of Lübeck, University Medical Center Schleswig-Holstein, Ratzeburger Allee 160, 23538 Lübeck, Germany.
  • 5 Department of Pharmacology, Faculty of Medicine, University of Latvia, Jelgavas iela 3, 1004 Riga, Latvia.
  • 6 Department of Neurobiology, The Georg S. Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv 6997801, Israel.
PMID: 36983062 DOI: 10.3390/ijms24065992
Abstract

Neuroinflammation and brain lipid imbalances are observed in Alzheimer's disease (AD). Tumor necrosis factor-α (TNFα) and the liver X receptor (LXR) signaling pathways are involved in both processes. However, limited information is currently available regarding their relationships in human brain pericytes (HBP) of the neurovascular unit. In cultivated HBP, TNFα activates the LXR pathway and increases the expression of one of its target genes, the transporter ATP-binding cassette family A member 1 (ABCA1), while ABCG1 is not expressed. Apolipoprotein E (APOE) synthesis and release are diminished. The Cholesterol efflux is promoted, but is not inhibited, when ABCA1 or LXR are blocked. Moreover, as for TNFα, direct LXR activation by the agonist (T0901317) increases ABCA1 expression and the associated Cholesterol efflux. However, this process is abolished when LXR/ABCA1 are both inhibited. Neither the other ABC transporters nor the SR-BI are involved in this TNFα-mediated lipid efflux regulation. We also report that inflammation increases ABCB1 expression and function. In conclusion, our data suggest that inflammation increases HBP protection against xenobiotics and triggers an LXR/ABCA1 independent Cholesterol release. Understanding the molecular mechanisms regulating this efflux at the level of the neurovascular unit remains fundamental to the characterization of links between neuroinflammation, Cholesterol and HBP function in neurodegenerative disorders.

Keywords

ABCA1; ABCB1; LXR; TNFα; brain pericytes; cholesterol metabolism.

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