C-Y.NG1, K-L.LEE1, M.D.MUTHIAH2, K-X.WU1, F.W.J.CHIOH1, K.TAN1, G.S.S.TING3, A.SHABBIR3, L.W.MUN3, Z.S.LOW1, Q.CHEN4, N.S.TAN1, H.H.NG5, Y.Y.DAN3, C.CHEUNG1
Nanyang Technological University1, National University of Singapore2, National University Hospital3, Institute of Molecular and Cell Biology4, Genome Institute of Singapore5
Cardiovascular events are often the fundamental causes of death in non-alcoholic fatty liver disease (NAFLD) patients, rather than complications in the liver. Mechanisms between cardiovascular disease and NAFLD however remains unknown. We therefore investigated the molecular underpinning of endothelial activation in NAFLD.
Here, we harnessed the replicative potential of blood outgrowth endothelial cells (BOECs) to develop personalised endothelial models from NAFLD and healthy subjects.
Transcriptomic analysis revealed an up-regulation of chemotaxis in the NAFLD BOECs, with CXCL12 being the more prominent one among the chemokines. Such an elevation of CXCL12 was also found in the aortae and liver vasculatures of our diet-induced NAFLD murine models. Accordingly, a higher number of leukocytes was recruited toward and adhered to NAFLD BOECs than healthy BOECs. We then performed immunoprofiling of NAFLD patients and uncovered an intensification of T cells. NAFLD BOECs appeared to be selective in recruiting CD4 over CD8 T cells. This recruitment was lowered by interfering the CXCL12-CXCR4 axis with the inhibitor AMD3100, thus highlighting the crucial role of CXCL12 in linking up endothelial activation and NAFLD. Lastly, we validated the occurrence of endothelial injury in NAFLD patients as indicated by a three-fold increase in circulating endothelial cells in their blood circulation.
Activated endothelial cells in NAFLD may provide a chemokine milieu, which promote interactions with leukocytes that subsequently lead to endothelial injury. Our work provides insights for modulation of endothelial cell-leukocyte crosstalk as an avenue for mitigating cardiovascular complications in NAFLD.