Fatty Acids Change the Conformation of Uncoupling Protein 1 (UCP1)

Divakaruni, Ajit S.; Humphrey, Dickon M.; Brand, Martin D.

doi:10.1074/jbc.m112.381780

Cited by 53 publications

(39 citation statements)

References 43 publications

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“…Specifically, LCFAs released by lipolysis of BAT lipid droplets upon adrenergic stimulation, activate UCP1-mediated thermogenesis 107 . These mechanisms were largely unknown, but several hypotheses exist including: 1) allosteric binding of LCFAs to an H+ or OH-uniporter channel, 2) LCFAs binding to the pore of UCP1 and regulating its function, or 3) UCP1 as an LCFA anion carrier bringing them outside the mitochondria to bind protons, or 4) FAs induce a conformational change in UCP1 (summarized in 109 ). A recent approach used patch-clamp to measure the UCP1 currents in the native inner mitochondrial membrane of BAT, and found that UCP1 has no constitutive activity (likely due to purine inhibition) until it is activated by LCFA generated within the inner mitochondrial membrane, which bind to the cytosolic side of UCP1 106 .…”

Section: Box1: Fuel Switchingmentioning

confidence: 99%

Brown fat fuel utilization and thermogenesis

Townsend¹,

Tseng²

2014

Trends in Endocrinology & Metabolism

284

248

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Brown adipose tissue (BAT) dissipates energy as heat to maintain optimal thermogenesis and to contribute to energy expenditure, in rodents and possibly humans. The energetic processes executed by BAT require a readily available fuel supply, which includes glucose and fatty acids (FAs). FAs become available by cellular uptake, de novo lipogenesis, and from multilocular lipid droplets in brown adipocytes. BAT also possesses a great capacity for glucose uptake and metabolism, and an ability to regulate insulin sensitivity. These properties make BAT an appealing target for the treatment of obesity, diabetes and other metabolic disorders. Recent research has revealed a better understanding of the processes of fuel utilization carried out by brown adipocytes, which is the focus of the current review.

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Section: Box1: Fuel Switchingmentioning

confidence: 99%

Brown fat fuel utilization and thermogenesis

Townsend¹,

Tseng²

2014

Trends in Endocrinology & Metabolism

284

248

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“…Alternatively, patch-clamp studies with mitochondrial inner membranes suggest that either protonated or deprotonated fatty acid species can be transported by UCP1, which remain bound to the protein in the transport cycle to give a net proton transfer (9). During activation, fatty acids may compete with nucleotide binding directly, or indirectly through changes in the protein, as indicated by experiments with isolated mitochondria (12,13). Claims of the involvement of other metabolites (e.g., ubiquinone-10 or 4-hydroxy-2-nonenal) in UCP1 activation have largely been refuted (14,15).…”

mentioning

confidence: 99%

Uncoupling protein 1 binds one nucleotide per monomer and is stabilized by tightly bound cardiolipin

Lee

Willers

Kunji

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

122

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Uncoupling protein 1 (UCP1) catalyzes fatty acid-activated, purine nucleotide-sensitive proton leak across the mitochondrial inner membrane of brown adipose tissue to produce heat, and could help combat obesity and metabolic disease in humans. Studies over the last 30 years conclude that the protein is a dimer, binding one nucleotide molecule per two proteins, and unlike the related mitochondrial ADP/ATP carrier, does not bind cardiolipin. Here, we have developed novel methods to purify milligram amounts of UCP1 from native sources by using covalent chromatography that, unlike past methods, allows the protein to be prepared in defined conditions, free of excess detergent and lipid. Assessment of purified preparations by TLC reveal that UCP1 retains tightly bound cardiolipin, with a lipid phosphorus content equating to three molecules per protein, like the ADP/ATP carrier. Cardiolipin stabilizes UCP1, as demonstrated by reconstitution experiments and thermostability assays, indicating that the lipid has an integral role in the functioning of the protein, similar to other mitochondrial carriers. Furthermore, we find that UCP1 is not dimeric but monomeric, as indicated by size exclusion analysis, and has a ligand titration profile in isothermal calorimetric measurements that clearly shows that one nucleotide binds per monomer. These findings reveal the fundamental composition of UCP1, which is essential for understanding the mechanism of the protein.Our assessment of the properties of UCP1 indicate that it is not unique among mitochondrial carriers and so is likely to use a common exchange mechanism in its primary function in brown adipose tissue mitochondria.

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“…Dieses ist auf der inneren Mitochondrienmembran lokalisiert und nimmt etwa 5% der gesamten Mitochondrienmasse ein (16). Der Kältereiz wird vom sympathischen Nervensystem an das braune Fettgewebe durch Ausschüttung von Noradrenalin weitergeleitet, wodurch in den Adipozyten Fettsäuren freigesetzt werden, die die Aktivität von UCP1 stimulieren (17). Nach seiner Aktivierung entkoppelt UCP1 den von der Atmungskette aufgebauten Protonengradienten von der ATP-Synthese, indem es Protonen über die innere Mitochondrienmembran mit dem Gradienten in die mitochondriale Matrix transportiert.…”

Section: Funktionen Des Braunen Fettgewebesunclassified

True Colours – Heterogenität des Fettgewebes

Fischer‐Posovszky¹,

Tews²

2018

Adipositas - Ursachen, Folgeerkrankungen, Therapie

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ZusammenfassungDas Fettgewebe ist ein dynamisches endokrines Organ. Es spiegelt die Energiehomöostase des Körpers wider und steht über seine Sekretionsprodukte in ständigem Informationsaustausch mit anderen Organsystemen. Das Fettgewebe zeichnet sich durch eine beachtliche anatomische, zelluläre und funktionelle Heterogenität aus, welche sich in einer Vielzahl unterschiedlicher Typen von Fettzellen ausdrückt. Dieser Übersichtsartikel stellt die verschiedenen „Farbnuancen” des Fettgewebes vor und diskutiert ihre funktionelle Relevanz im Organismus.

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Fatty Acids Change the Conformation of Uncoupling Protein 1 (UCP1)

Cited by 53 publications

References 43 publications

Brown fat fuel utilization and thermogenesis

Brown fat fuel utilization and thermogenesis

Uncoupling protein 1 binds one nucleotide per monomer and is stabilized by tightly bound cardiolipin

True Colours – Heterogenität des Fettgewebes

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