Targeting the vasculature in cardiometabolic disease

Figure 1. Schematic overview of systemic lipoprotein metabolism. Triglyceride-rich lipoproteins such as VLDL and chylomicron (CM) are produced by the liver and gut, respectively, which distribute FFAs to various metabolic tissue(s) like muscle, heart, and adipose by interacting with the GPIHBP1-bound endothelial LPL enzyme. LPL activity is regulated by secreted ANGPTL3, ANGPTL4, and ANGPTL8. In subsequent peripheral lipolysis, VLDL and CM are converted into intermediate-density lipoprotein (IDL) and chylomicron remnants (CMRs). In the liver, HL liberates FFAs from IDL and converts them into LDL particles. HL activity is inhibited by ANGPTL4. The liver clears a large portion of remnants (LDL and CMRs) via hepatic receptors (LDLR and LRP1). Under hyperlipidemic conditions, some fractions of LDL or CMRs accumulate and oxidize in the subendothelial space of a large artery, which is subsequently taken up by macrophages that develop into foam cells within atherosclerotic plaques. Liver-derived Apo M complexed with sphingosine-1-phosphate (S1P) on HDL may modulate atherosclerotic plaque progression, first by interacting with endothelial S1P receptors (S1PRs) to maintain vascular integrity and…

Figure 2. Schematic overview of endothelial microvasculature in fatty acid uptake and systemic metabolism. FFAs, either bound to albumin, or derived from LPL-mediated hydrolysis of circulating TRLs, traverse the endothelium by passive diffusion (flip-flop), receptor-mediated uptake (via CD36), and/or vectorial transport (via FATP4). FATP3 and ACSL1 and other acyl-CoA synthases likely facilitate vectorial transport, and mitochondrial ATP also appears to be important. ECs contain machinery to esterify FFAs into LDs, a DGAT1-dependent process that may protect ECs from ER stress. Conversely, LDs may be hydrolyzed, a largely ATGL-dependent process that liberates FFAs for mitochondrial oxidation and/or parenchymal delivery. Circulating bioactive molecules such as apelin can regulate FABP4 transcription, and bioactive molecules released from muscle cells, including 3-HIB and VEGFB, can regulate FATP3 and FATP4 expression. In addition, adipose tissue–derived ANGPT2 can activate endothelial α5β1 signaling to trigger FFA transport via CD36 and FATP3 into superficial adipose tissue. Adipose tissue–derived VEGFA signals via EC VEGFR2 to support both WAT and BAT angiogenesis and also plays a role in…