Endothelial CEPT1 Regulates Hepatic MTTP-Mediated Lipid Metabolism and Impacts Aortic Atherosclerosis

Zayed, M. A.; Ibrahim, D.; Hafezi, S.; Khan, T. J.; Kuziez, I.; Belaygorod, L.; Yang, C.; Engel, C.; Li, C.; Jin, X.; Braash, M.; Zhang, Z.; Lin, Y.; Adak, S.; Semenkovich, C. F.

doi:10.1101/2025.09.21.677657

bioRxiv · 10.1101/2025.09.21.677657

Endothelial CEPT1 Regulates Hepatic MTTP-Mediated Lipid Metabolism and Impacts Aortic Atherosclerosis

Zayed, M. A.·Ibrahim, D.·Hafezi, S.·Khan, T. J.·Kuziez, I.·Belaygorod, L.·Yang, C.·Engel, C.·Li, C.·Jin, X.·Braash, M.·Zhang, Z.·Lin, Y.·Adak, S.·Semenkovich, C. F.

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Abstract

BackgroundThe regulation of hepatic lipid metabolism by vascular endothelial factors remains poorly characterized, despite its relevance to atherosclerosis and steatosis. Microsomal triglyceride transfer protein (MTTP) is essential for hepatic lipid metabolism, but its regulation by endothelial cells has not been previously investigated. ObjectiveThis study examined whether endothelial choline ethanolamine phosphotransferase 1 (CEPT1) modulates hepatic MTTP activity, impacting systemic lipid homeostasis and aortic plaque formation. Methods and ResultsHuman steatotic liver samples exhibited reduced CEPT1 and MTTP protein levels, correlating with diminished lipid exports. In mice, endothelial-specific Cept1 knockdown decreased hepatic MTTP expression, reduced serum triglyceride and cholesterol levels, and markedly attenuated aortic atherosclerosis without evidence of fat malabsorption. In vitro, endothelial CEPT1 silencing suppressed MTTP activity in co-cultured hepatocytes via a paracrine mechanism involving peroxisome proliferator-activated receptor (PPAR) signaling, which was rescued by fenofibrate treatment. Aortic histology confirmed reduced plaque burden and macrophage infiltration in CEPT1-deficient mice. ConclusionsEndothelial CEPT1 critically regulates hepatic MTTP through a paracrine axis, influencing lipid metabolism and atherogenesis. Targeting endothelial CEPT1 may represent a novel therapeutic approach to reduce steatosis and vascular atherosclerosis.

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Zayed, M. A., Ibrahim, D., Hafezi, S., Khan, T. J., Kuziez, I., Belaygorod, L., Yang, C., Engel, C., Li, C., Jin, X., Braash, M., Zhang, Z., Lin, Y., Adak, S., Semenkovich, C. F.. 2025-09-21. Endothelial CEPT1 Regulates Hepatic MTTP-Mediated Lipid Metabolism and Impacts Aortic Atherosclerosis. https://doi.org/10.1101/2025.09.21.677657

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