Local Mitochondrial ATP Production Regulates Endothelial Fatty Acid Uptake and Transport.

Cell Metabolism
Ayon IbrahimZoltan Arany

Abstract

Most organs use fatty acids (FAs) as a key nutrient, but little is known of how blood-borne FAs traverse the endothelium to reach underlying tissues. We conducted a small-molecule screen and identified niclosamide as a suppressor of endothelial FA uptake and transport. Structure/activity relationship studies demonstrated that niclosamide acts through mitochondrial uncoupling. Inhibitors of oxidative phosphorylation and the ATP/ADP translocase also suppressed FA uptake, pointing principally to ATP production. Decreasing total cellular ATP by blocking glycolysis did not decrease uptake, indicating that specifically mitochondrial ATP is required. Endothelial FA uptake is promoted by fatty acid transport protein 4 (FATP4) via its ATP-dependent acyl-CoA synthetase activity. Confocal microscopy revealed that FATP4 resides in the endoplasmic reticulum (ER), and that endothelial ER is intimately juxtaposed with mitochondria. Together, these data indicate that mitochondrial ATP production, but not total ATP levels, drives endothelial FA uptake and transport via acyl-CoA formation in mitochondrial/ER microdomains.

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Citations

Feb 5, 2021·Circulation Research·Nada A AbumradIra J Goldberg
Dec 17, 2020·International Journal of Molecular Sciences·Emelie Lassén, Ilse S Daehn
Dec 29, 2020·IUBMB Life·Ana Victoria Lechuga-ViecoJosé Antonio Enríquez
Feb 25, 2021·The Biochemical Journal·Megan C BlairZoltan Arany
Jun 16, 2021·Atherosclerosis·Ira J GoldbergNada A Abumrad
Aug 7, 2020·Cell Metabolism·Nabil E BoutagyWilliam C Sessa
Apr 21, 2021·Blood·Victoria da Silva-DizDaniel Herranz
Dec 7, 2021·Obesity Reviews : an Official Journal of the International Association for the Study of Obesity·Anna IoannidouCarolina E Hagberg

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