Regulation of endothelial fatty acid uptake by VEGF-B : mechanisms and therapeutic implications

The incidence of type 2 diabetes (T2D) and its co-morbidities including ischemic stroke and diabetic kidney disease (DKD) are increasing at an alarming rate. T2D patients typically present with high levels of circulating fatty acids (FAs) in the blood as well as increased tissue lipid droplet (LD) accumulation resulting in insulin resistance. The transport of FAs from blood to tissues therefore plays a key role in the development of insulin resistance and T2D. The endothelium facilitates FA and glucose uptake and transport from blood to the underlying tissues, but the contribution of dysregulated endothelial FA transport to ischemic stroke and DKD remain unclear. The metabolic pathways that govern endothelial FA uptake are also poorly understood since endothelial cells (ECs) rely almost exclusively on anaerobic glycolysis for energy consumption while mitochondrial ATP synthesis has been suggested to facilitate FA uptake.

In this thesis, we demonstrate that lipolysis drives endothelial FA uptake by promoting mitochondrial oxidation of FAs for ATP production. We provide evidence that both vascular endothelial growth factor-B (VEGF-B) stimulation and oleic acid exposure drive FA uptake by activating lipolysis. Conversely, VEGF-B and oleic acid decreased endothelial glucose uptake by modulating glucose transporter 1-dependent transport. In vivo, elevated circulating FA levels correlated with increased FA uptake and reduced glucose uptake to brain. We further discovered that high-fat diet feeding exacerbates cerebrovascular LD accumulation acutely after ischemic stroke, and that this was associated with increased vascular permeability, intracerebral hemorrhage incidence and infarct size. Intriguingly, we also discovered an unexpected pro-lipolytic activity of the thrombolytic agent tissue plasminogen activator in adipose tissue. Treatment with neutralizing antibodies against VEGF-B inhibited adipose lipolysis and the subsequent rise in circulating FAs, improving the outcome after ischemic stroke. Similarly, T2D animal models and transgenic animals that overexpress VEGF-B in podocytes accumulate LDs in the glomeruli of the kidney resulting in DKD- associated pathology, while systemic inhibition of VEGF-B reduced glomerular LD accumulation and ameliorated DKD progression in T2D animals.

Collectively, our data suggests that targeting endothelial FA transport both locally and systemically via VEGF-B inhibition reduces ectopic LD accumulation in brain and kidney correlating with improved outcome after ischemic stroke and ameliorated DKD-associated pathology.

List of scientific papers

I. Benjamin Heller Sahlgren, Jil Protzmann, Ulf Eriksson, Linda Fredriksson and Ingrid Nilsson. Endothelial fatty acid uptake is activated by lipolysis and depends on lipid droplet metabolism. 2024. [Manuscript]

II. Christine Moessinger, Ingrid Nilsson, Lars Muhl, Manuel Zeitelhofer, Benjamin Heller Sahlgren, Josefin Skogsberg, Ulf Eriksson. VEGF-B signaling impairs endothelial glucose transcytosis by decreasing membrane cholesterol content. EMBO Reports, 2020, 21, 7, e49343. https://doi.org/10.15252/embr.201949343

III. Ingrid Nilsson, Enming J. Su, Linda Fredriksson, Benjamin Heller Sahlgren, Zsuzsa Bagoly, Christine Moessinger, Christina Stefanitsch, Frank Chenfei Ning, Manuel Zeitelhofer, Lars Muhl, Anna-Lisa E. Lawrence, Pierre D. Scotney, Li Lu, Erik Samén, Heidi Ho, Richard F. Keep, Robert L. Medcalf, Daniel A. Lawrence and Ulf Eriksson. Thrombolysis exacerbates cerebrovascular injury after ischemic stroke via a VEGF-B dependent effect on adipose lipolysis. 2024. [Manuscript]

IV. Annelie Falkevall, Annika Mehlem, Isolde Palombo, Benjamin Heller Sahlgren, Lwaki Ebarasi, Liqun He, A. Jimmy Ytterberg, Hannes Olauson, Jonas Axelsson, Birgitta Sundelin, Jaakko Patrakka, Pierre Scotney, Andrew Nash and Ulf Eriksson. Reducing VEGF-B Signaling Ameliorates Renal Lipotoxicity and Protects against Diabetic Kidney Disease. Cell Metabolism, 2017, 25, 713-726. https://doi.org/10.1016/j.cmet.2017.01.004