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Review
, 1790 (10), 1149-60

Alpha-lipoic Acid as a Dietary Supplement: Molecular Mechanisms and Therapeutic Potential

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Review

Alpha-lipoic Acid as a Dietary Supplement: Molecular Mechanisms and Therapeutic Potential

Kate Petersen Shay et al. Biochim Biophys Acta.

Abstract

Alpha-lipoic acid (LA) has become a common ingredient in multivitamin formulas, anti-aging supplements, and even pet food. It is well-defined as a therapy for preventing diabetic polyneuropathies, and scavenges free radicals, chelates metals, and restores intracellular glutathione levels which otherwise decline with age. How do the biochemical properties of LA relate to its biological effects? Herein, we review the molecular mechanisms of LA discovered using cell and animal models, and the effects of LA on human subjects. Though LA has long been touted as an antioxidant, it has also been shown to improve glucose and ascorbate handling, increase eNOS activity, activate Phase II detoxification via the transcription factor Nrf2, and lower expression of MMP-9 and VCAM-1 through repression of NF-kappa B. LA and its reduced form, dihydrolipoic acid, may use their chemical properties as a redox couple to alter protein conformations by forming mixed disulfides. Beneficial effects are achieved with low micromolar levels of LA, suggesting that some of its therapeutic potential extends beyond the strict definition of an antioxidant. Current trials are investigating whether these beneficial properties of LA make it an appropriate treatment not just for diabetes, but also for the prevention of vascular disease, hypertension, and inflammation.

Figures

Figure 1
Figure 1
The R and S enantiomers of lipoic acid.
Figure 2
Figure 2
Lipoic acid and its reduced form, dihydrolipoic acid, with the 5 most common metabolites.
Figure 3
Figure 3
Proposed action of LA for induction of Phase II genes through Nrf2-mediated transcription. LA may oxidize critical thiols on the Keap1 dimer to halt Nrf2 degradation, and to prevent Keap1 from binding newly synthesized Nrf2. LA may also activate protein kinase signaling pathways that cause phosphorylation of Nrf2 on Ser40. This is the event that allows it to dissociate from Keap1 [68, 69]. Nrf2 can then localize to the nucleus and bind to the ARE, promoting transcription of genes for the Phase II detoxification response.
Figure 4
Figure 4
Role of lipoic acid in IR/PI3K/Akt-dependent activation of glucose uptake in skeletal muscle Diesel et al. put forth the notion that LA may directly bind to and activate the tyrosine kinase domain of the insulin receptor (IR) b-subunit [84]. The authors based their claim on a computer modeling of the IR tyrosine kinase domain where LA would theoretically fit in a pocket located between Leu1133 and Phe1186. In contrast to a direct role of LA on IR, LA was proposed to oxidize critical cysteine thiols in protein tyrosine phosphatase B1 (PTPB1) thereby preventing the PTPB1-mediated inhibitory dephosphorylation of the IR tyrosine kinase domain [79]. Alternatively, LA was found to enhance the insulin receptor substrate 1 (IRS1) protein expression in muscle of obese Zucker rats and association of IRS1 with the p85 regulatory subunit of PI3K [78]. Moreover, the well-established regulation of muscle glucose uptake by exercise/muscle contraction through protein kinases, including AMP-activated protein kinase (AMPK) [85, 86] is of interest because LA activates peripheral AMPK [87, 89, 139]. Thus, through AMPK, LA is thought to i) induce the phosphorylation of IRS1 Ser789 and activation of the IRS1/PI3K signaling [90, 91] and ii) stimulate GLUT4 translocation via inactivation of the Akt substrate of 160 kDa (AS160) independently of the IRS1/PI3K/Akt signaling cascade [92, 93]. The effects of LA on IR/IRS1 will increase IRS1 association with PI3K and PI3K activity in the membrane environment. PtdIns-3,4,5-P3 (PIP3) production by PI3K recruits PtdIns-dependent kinase 1 (PDK1) to the membrane by Pleckstrin Homology domain:PIP3 interaction and stimulates PDK1-mediated phosphorylation of Akt Thr308. Following Ser473 phosphorylation, fully activated Akt regulates the trafficking of GLUT4 between storage vesicles and the plasma membrane through a mechanism involving the phosphorylation of AS160. In its active dephosphorylated form, AS160 inhibits GLUT4 vesicle trafficking to the plasma membrane by preventing Rab-GTP association with the vesicle. Akt-mediated phosphorylation of AS160 opposes the repressor role of AS160 and allows Rab-GTP binding to the GLUT4 vesicle. Domain structure analysis revealed that AS160 has a Rab-GAP (GTPase-activating protein) domain at the C-terminus and that the Rab-GAP activity promotes the hydrolysis of small G proteins Rab-GTP to Rab-GDP [140]. In its inactive GDP-loaded form, Rab is unable to associate with the GLUT4 vesicle nor elicit translocation to the plasma membrane. But Akt-mediated phosphorylation of AS160 inactivates the Rab-GAP activity of AS160 thus favoring the association of GTP-loaded active form of Rab with the GLUT4 vesicle.
Figure 5
Figure 5
Proposed biological actions of lipoic acid

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