Endothelial lipid droplets suppress eNOS to link high fat consumption to blood pressure elevation
Boa Kim, … , Garret A. FitzGerald, Zoltan Arany
Boa Kim, … , Garret A. FitzGerald, Zoltan Arany
Published October 12, 2023
Citation Information: J Clin Invest. 2023;133(24):e173160. https://doi.org/10.1172/JCI173160.
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Research Article Cardiology

Endothelial lipid droplets suppress eNOS to link high fat consumption to blood pressure elevation

Abstract

Metabolic syndrome, today affecting more than 20% of the US population, is a group of 5 conditions that often coexist and that strongly predispose to cardiovascular disease. How these conditions are linked mechanistically remains unclear, especially two of these: obesity and elevated blood pressure. Here, we show that high fat consumption in mice leads to the accumulation of lipid droplets in endothelial cells throughout the organism and that lipid droplet accumulation in endothelium suppresses endothelial nitric oxide synthase (eNOS), reduces NO production, elevates blood pressure, and accelerates atherosclerosis. Mechanistically, the accumulation of lipid droplets destabilizes eNOS mRNA and activates an endothelial inflammatory signaling cascade that suppresses eNOS and NO production. Pharmacological prevention of lipid droplet formation reverses the suppression of NO production in cell culture and in vivo and blunts blood pressure elevation in response to a high-fat diet. These results highlight lipid droplets as a critical and unappreciated component of endothelial cell biology, explain how lipids increase blood pressure acutely, and provide a mechanistic account for the epidemiological link between obesity and elevated blood pressure.

Authors

Boa Kim, Wencao Zhao, Soon Y. Tang, Michael G. Levin, Ayon Ibrahim, Yifan Yang, Emilia Roberts, Ling Lai, Jian Li, Richard K. Assoian, Garret A. FitzGerald, Zoltan Arany

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Figure 1

Endothelial deletion of Atgl phenocopies fat intake–induced accumulation of LDs and rise in BP.

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Endothelial deletion of Atgl phenocopies fat intake–induced accumulation...
(A) Experimental setup for administration of NC, HFD, HSD, or HFD+HSD in WT C57BL/6J mice, while monitoring BP by noninvasive telemetry. (B) Elevation of SBP during active phase (7 pm to 7 am) under indicated diet for 7 days. n = 11 (group 1); n = 4 (group 2). One-way ANOVA. (C and D) En face staining of thoracic aorta before and after olive oil gavage (10 mL/kg body weight) (C) or 5 hours of either NC or HFD ad libitum feeding (D) in WT C57BL/6J mice. BODIPY staining (green) indicates neutral lipids, and CD31 (red) marks the endothelium. BODIPY-positive area in the endothelium is quantified (right panel). n = 4–7 (C); n = 5 (D). **P < 0.01, t test. (E) Schematic of the role of ATGL in TG hydrolysis, yielding diacylglycerols (DG) and FFA. Deletion of ATGL leads to LD accumulation. (F) WB (upper panel) and qPCR (lower panel) of isolated aortic ECs from WT versus Atgl ECKO mice. n = 4. **P < 0.01, t test. (G) Whole-mount staining of portal vein, soleus, heart, and retina from fasted WT versus Atgl ECKO mice, imaged with BODIPY (green), anti-CD31 immunohistochemistry or IsoB4 lectin (red), and DAPI (blue). For the retina staining, side views of Z-stacked images are shown on the right, and zoomed-in images are shown below. BODIPY-positive area in the endothelium is quantified (right panel). n = 4–5. **P < 0.01, t test. (H) Left panel: experimental setup for administration of NC or HFD in WT versus Atgl ECKO mice. Right panel: average active-phase SBP in each genotype while provided with the indicated diet. n = 9 (WT); n = 12 (Atgl ECKO). *P < 0.05, 1-way ANOVA.