α-Lipoic Acid as a Directly Binding Activator of the Insulin Receptor:  Protection from Hepatocyte Apoptosis

Diesel, Britta; Kulhanek-Heinze, Stefanie; Höltje, Monika; Brandt, Birte; Höltje, § Hans-Dieter; Vollmar, and Angelika M.; Kiemer, Alexandra K.

doi:10.1021/bi602547m

Cited by 82 publications

(49 citation statements)

References 37 publications

(53 reference statements)

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“…Similar results have only recently been found in hepatocytes, where inhibition of apoptosis by ␣-lipoic acid as well is associated with activation of the PI 3-kinase/Akt pathway (18).…”

Section: Discussionsupporting

confidence: 85%

R-(+)-α-lipoic acid inhibits endothelial cell apoptosis and proliferation: involvement of Akt and retinoblastoma protein/E2F-1

Artwohl¹,

Muth²,

Kosulin³

et al. 2007

American Journal of Physiology-Endocrinology and Metabolism

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Lipoic acid was recently demonstrated to improve endothelial dysfunction or retinopathy not only in rats but also in diabetic patients. We tested the hypothesis that R-(+)-α-lipoic acid (LA) directly affects human endothelial cell (EC) function (e.g., apoptosis, proliferation, and protein expression), independent of the cells' vascular origin. Macrovascular EC (macEC), isolated from umbilical (HUVEC) and adult saphenous veins and from aortae, as well as microvascular EC (micEC) from retinae, skin, and uterus, were exposed to LA (1 μmol/l–1 mmol/l) with/without different stimuli (high glucose, TNF-α, VEGF, wortmannin, LY-294002). Apoptosis, proliferation, cell cycle distribution, and protein expression were determined by DNA fragmentation assays, [3H]thymidine incorporation, FACS, and Western blot analyses, respectively. In macro- and microvascular EC, LA (1 mmol/l) reduced ( P < 0.05) basal (macEC, −36 ± 4%; micEC, −46 ± 6%) and stimulus-induced (TNF-α: macEC, −75 ± 11%; micEC, −68 ± 13%) apoptosis. In HUVEC, inhibition of apoptosis by LA (500 μmol/l) was paralleled by reduction of NF-κB. LA's antiapoptotic activity was reduced by PI 3-kinase inhibitors (wortmannin, LY-294002), being in line with LA-induced Akt phosphorylation (Ser437, +159 ± 43%; Thr308, +98 ± 25%; P < 0.01). LA (500 μmol/l) inhibited ( P < 0.001) proliferation of macEC (−29 ± 3%) and micEC (−29 ± 3%) by arresting the cells at the G1/S transition due to an increased ratio of cyclin E/p27Kip (4.2-fold), upregulation of p21WAF-1/Cip1 (+104 ± 21%), and reduction of cyclin A (−32 ± 11%), of hyperphosphorylated retinoblastoma protein (macEC: −51 ± 7%; micEC: −50 ± 15%), and of E2F-1 (macEC: −48 ± 3%; micEC: −31 ± 10%). LA's ability to inhibit apoptosis and proliferation of ECs could beneficially affect endothelial dysfunction, which precedes manifestation of late diabetic vascular complications.

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“…Similar results have only recently been found in hepatocytes, where inhibition of apoptosis by ␣-lipoic acid as well is associated with activation of the PI 3-kinase/Akt pathway (18).…”

Section: Discussionsupporting

confidence: 85%

R-(+)-α-lipoic acid inhibits endothelial cell apoptosis and proliferation: involvement of Akt and retinoblastoma protein/E2F-1

Artwohl¹,

Muth²,

Kosulin³

et al. 2007

American Journal of Physiology-Endocrinology and Metabolism

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“…In this regard, we have demonstrated for the first time that LA prevents degradation of IRS proteins induced by PA. In a previous study, it was shown that the protection of LA against TNFĮ/actinomycin D-mediated apoptosis was due to a direct activation of the IR [83].…”

Section: Discussionmentioning

confidence: 99%

Essential role of Nrf2 in the protective effect of lipoic acid against lipoapoptosis in hepatocytes

Valdecantos

Prieto-Hontoria

Pardo

et al. 2015

Free Radical Biology and Medicine

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“…23 Regarding the other examined proteins (1ZSX, 1Q5M and 1CQZ), not all CP-CIE values were negative, and consequently, the interactions are not totally favorable, although the affinity value calculated for 1ZSX was the same as that obtained for 1HS6.…”

Section: Resultsmentioning

confidence: 78%

“…[20][21][22] The biochemical importance of ALA is mainly represented by its participation as a cofactor in several biological processes, and due to its antiapoptotic action via activation of the insulin receptor/PI3-kinase/Akt pathway. 23 Nowadays, in silico screening has made possible to find suitable biological targets for particular compounds. Target Fishing Dock (TarFisDock) is a web server that docks small molecules with protein structures in the Potential Drug Target Database (PDTD), as a tool to discover new drug targets.…”

Section: -16mentioning

confidence: 99%

Searching of protein targets for alpha lipoic acid

Maldonado-Rojas¹,

Olívero-Verbel²,

Ortega-Zúñiga³

2011

J. Braz. Chem. Soc.

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Ácido alfa lipóico (ALA) é um dos oxidantes mais poderosos e um cofactor em complexos enzimáticos, apesar de seus mecanismos ainda não serem conhecidos. A pesquisa por alvos proteicos de ALA é fundamental para compreender seus processos de sinalização. Uma abordagem bioinformática foi usada a fim de se encontrar alvos hipotéticos para ALA usando o servidor Target Fishing Dock (TarFisDock). Contagens de afinidade para os melhores resultados foram calculadas pelo AutoDock Vina. Alvos relevantes incluíram leucotrieno A4 hidrolase, canal de potássio voltagem-dependente, alfa-hidroxiesteróide desidrogenase, epóxido hidrolase, proteínas estas envolvidas no câncer, diabetes, desordens neurológica e cardiovascular. As energias de interação corrigidas segundo padrão conterpoise foram calculadas para proteínas que ligam R-ALA, e mostraram interações R-ALA-resíduos favoráveis. A sobreposição de R-ALA com inibidores conhecidos daquelas proteínas, permitu concluir que R-ALA adota diferentes conformações espaciais em seus sítios de ligação, podendo ser um inibidor fraco plausível destes alvos e, portanto, este efeito deveria ser considerado quando da realização de estudos sobre seus efeitos bioquímicos.Alpha lipoic acid (ALA) is one of the most powerful antioxidants and a cofactor in enzyme complexes, although its mechanisms are still unknown. The search for protein targets of ALA is fundamental to understand its signaling pathways. A bioinformatics approach was used to find hypothetical targets for ALA using the Target Fishing Dock Server (TarFisDock). Affinity scores for the best hits were calculated by AutoDock Vina. Relevant targets included leukotriene A4 hydrolase, voltage gated potassium channel, alpha hydroxysteroid dehydrogenase and epoxide hydrolase, proteins involved in cancer, diabetes, and neurological and cardiovascular disorders. The counterpoise-corrected interaction energies calculated for proteins that bind R-ALA showed favorable interactions R-ALA-residues. Superpositioning of R-ALA with known inhibitors of those proteins, together with the finding that R-ALA adopts different spatial conformations in their binding sites, suggests R-ALA could be a plausible weak inhibitor of these targets, and this effect should be considered when studying its biochemical effects.

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α-Lipoic Acid as a Directly Binding Activator of the Insulin Receptor: Protection from Hepatocyte Apoptosis

Cited by 82 publications

References 37 publications

R-(+)-α-lipoic acid inhibits endothelial cell apoptosis and proliferation: involvement of Akt and retinoblastoma protein/E2F-1

R-(+)-α-lipoic acid inhibits endothelial cell apoptosis and proliferation: involvement of Akt and retinoblastoma protein/E2F-1

Essential role of Nrf2 in the protective effect of lipoic acid against lipoapoptosis in hepatocytes

Searching of protein targets for alpha lipoic acid

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