Localizing Lipids

Science Signaling  13 Apr 2010:
Vol. 3, Issue 117, pp. ec108
DOI: 10.1126/scisignal.3117ec108

Although vascular endothelial growth factors (VEGFs) are known for their roles in angiogenesis, VEGF-B is poorly angiogenic in most tissues, and its biological function has been uncertain. Bioinformatics analyses led Hagberg et al. to the unexpected finding that Vegfb was coexpressed with mitochondrial genes, an observation they confirmed with quantitative polymerase chain reaction. Noting that VEGF-B is abundant in mitochondria-rich tissues that use fatty acids as an energy source (heart, brown adipose tissue, and oxidative skeletal muscle), the authors looked for effects of VEGF-B on endothelial cell handling of fatty acids. VEGF-B increased the abundance of fatty acid transport proteins (FATPs), and of their encoding mRNAs, in cultured endothelial cells and endothelial cell lines, an effect that was blocked by antibodies directed against VEGF receptor 1 (VEGFR1) and neuropilin 1 (NRP1). In vivo analyses of various knockout mice and mice injected with adenovirus encoding VEGFs, combined with analyses of isolated endothelial cells from wild-type and Vegfb–/– mice, indicated that VEGF-B signaled through VEGFR1 and NRP1 to increase the endothelial abundance of FATP3 and FATP4 in peripheral lipid-metabolizing tissues. Overexpression of FATP3 or FATP4 led to increased uptake of labeled long-chain fatty acids (LCFAs) in cultured endothelial cells, as did treatment with VEGF-B, whereas their knockdown attenuated VEGF-B’s ability to stimulate LCFA accumulation. VEGF-B also stimulated transport of LCFA across an endothelial monolayer separating two liquid compartments. Although Vegfb–/– mice showed normal intestinal adsorption of LCFA, their lipid disposition differed from that of wild-type mice, with less lipid accumulation in heart, brown adipose tissue, and muscle and more in white adipose tissue. The authors thus conclude that VEGF-B regulates endothelial fatty acid transport—and thereby lipid disposition—by stimulating FATP production and that identification of this role may lead to new therapeutic options in diseases associated with pathological accumulation of lipids.

C. E. Hagberg, A. Falkevall, X. Wang, E. Larsson, J. Huusko, I. Nilsson, L. A. van Meeteren, E. Samen, L. Lu, M. Vanwildemeersch, J. Klar, G. Genove, K. Pietras, S. Stone-Elander, L. Claesson-Welsh, S. Ylä-Herttuala, P. Lindahl, U. Eriksson, Vascular endothelial growth factor B controls endothelial fatty acid uptake. Nature 464, 917–921 (2010). [PubMed]