👤 Munichandra Tirumalasetty

Long-chain fatty acids in the blood are prevented from unfettered movement into nonfenestrated tissues or the arterial wall. During fasting, nonesterified FAs are released from adipose tissue into the circulation and bind to albumin, forming a complex >65 kDa, with limited ability to efficiently cross endothelial cell (EC) barriers without a specific receptor. For this reason, nonhepatic tissue distribution of circulating FA parallels EC expression of the FA-binding protein CD36 (cluster of differentiation 36). The deletion of CD36 in ECs reduces nonesterified FA uptake by the heart, muscle, and brown adipose tissue. The other major transport system for FAs is via lipoproteins. Circulating FAs are contained within TRLs (triglyceride-rich lipoproteins), chylomicrons during the postprandial period, and VLDL (very low-density lipoprotein) both postprandially and during fasting. LPL (lipoprotein lipase) on capillary ECs releases FAs from TRLs and likely allows their passage into tissues, in part, via a CD36-independent process. ECs can also internalize lipoprotein particles, followed by the transendothelial movement of lipids. In this review, we will discuss the pathways of EC uptake of FAs from circulation, how this process affects both EC and tissue biology, and the importance of these processes for systemic metabolism and vascular health. We will conclude with speculations on methods to modulate EC FA uptake and their implications for human health. Show less

Increased fasting and postprandial triglyceride levels are risk factors for cardiovascular disease (CVD). Partially metabolized triglyceride-rich lipoproteins (TRLs) termed remnants are created when intestinally-derived chylomicrons and liver secreted very low density lipoproteins (VLDLs) interact with lipoprotein lipase (LpL) situated on the luminal surface of capillary endothelial cells. Higher circulating remnant levels have been implicated as the reason for the relationship between TRL levels and CVD. We hypothesized that nascent lipoproteins not only remnants are atherogenic. To test this, we created mice with induced whole-body lipoprotein lipase (LpL) deficiency combined with LDL receptor (LDLR) deficiency. On an atherogenic Western-type diet (WD), male and female mice with induced global LpL deficiency (iLpl Show less

Movement of circulating lipids into tissues and arteries requires transfer across the endothelial cell (EC) barrier. This process allows the heart to obtain fatty acids, its chief source of energy, and apoB-containing lipoproteins to cross the arterial endothelial barrier, leading to cholesterol accumulation in the subendothelial space. Multiple studies have established elevated postprandial TRLs (triglyceride-rich lipoproteins) as an independent risk factor for cardiovascular disease. We explored how chylomicrons affect ECs and transfer their fatty acids across the EC barrier. We had reported that media from chylomicron-treated ECs lead to lipid droplet formation in macrophages. To determine the responsible component of this media, we assessed whether removing the extracellular vesicles (EVs) would obviate this effect. EVs from control and treated cells were then characterized by protein, lipid, and microRNA content. We also studied the EV-induced transcription changes in macrophages and ECs and whether knockdown of SR-BI (scavenger receptor-BI) altered these responses. In addition, using chylomicrons labeled with [ Chylomicron treatment of ECs led to an inflammatory response that included production of EVs that drove macrophage lipid droplet accumulation. The EVs contained little free fatty acids and triglycerides, but abundant phospholipids and diacylglycerols. In concert with this, [ EC chylomicron metabolism produces EVs that increase macrophage inflammation and create LDs. Media containing these EVs also increases EC inflammation, illustrating an autocrine inflammatory process. Fatty acids within chylomicron triglycerides are converted to phospholipids within EVs. Thus, EC uptake of chylomicrons constitutes an important pathway for vascular inflammation and tissue lipid acquisition. Show less

Movement of circulating lipids into tissues and arteries requires transfer across the endothelial cell barrier. This process allows the heart to obtain fatty acids (FAs), its chief source of energy and apolipoprotein B (apoB)-containing lipoproteins to cross the arterial endothelial barrier leading to cholesterol accumulation in the subendothelial space. Multiple studies have established elevated postprandial triglyceride-rich lipoproteins (TRLs) as an independent risk factor for cardiovascular disease (CVD). We explored how chylomicrons affect ECs and transfer their FAs across the EC barrier. We had reported that media from chylomicron-treated ECs leads to lipid droplet (LD) formation in macrophages. To determine the responsible component of this media, we assessed whether removing the extracellular vesicles (EVs) would obviate this effect. EVs from control and treated cells were then characterized by protein, lipid and microRNA (miR) content. We also studied the EV-induced transcription changes in macrophages and ECs and whether knockdown of scavenger receptor-BI (SR-BI) altered these responses. In addition, using chylomicrons labeled with [ Chylomicron treatment of ECs led to an inflammatory response that included production of EVs that drove macrophage LD accumulation. The EVs contained little free fatty acids and triglyceride, but abundant phospholipids and diacylglycerols. In concert with this, [ EC chylomicron metabolism produces EVs that increase macrophage inflammation and create LDs. Media containing these EVs also increases EC inflammation, illustrating an autocrine inflammatory process. FAs within chylomicron triglycerides are converted to phospholipids within EVs. Thus, EC uptake of chylomicrons constitutes an important pathway for vascular inflammation and tissue lipid acquisition. Show less