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Lipoic acid: energy metabolism and redox regulation of transcription and cell signaling.

Packer L, Cadenas E - J Clin Biochem Nutr (2010)

Bottom Line: The diversity of beneficial effects of lipoic acid in a variety of tissues can be mechanistically viewed in terms of thiol/disulfide exchange reactions that modulate the environment's redox and energy status.Lipoic acid-driven thiol/disulfide exchange reactions appear critical for the modulation of proteins involved in cell signaling and transcription factors.This review emphasizes the effects of lipoic acid on PI3K and AMPK signaling and related transcriptional pathways that are integrated by PGC-1α, a critical regulator of energy homoestasis.

View Article: PubMed Central - PubMed

Affiliation: Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, CA 90089, USA.

ABSTRACT
The role of R-α-lipoic acid as a cofactor (lipoyllysine) in mitochondrial energy metabolism is well established. Lipoic acid non-covalently bound and exogenously administered to cells or supplemented in the diet is a potent modulator of the cell's redox status. The diversity of beneficial effects of lipoic acid in a variety of tissues can be mechanistically viewed in terms of thiol/disulfide exchange reactions that modulate the environment's redox and energy status. Lipoic acid-driven thiol/disulfide exchange reactions appear critical for the modulation of proteins involved in cell signaling and transcription factors. This review emphasizes the effects of lipoic acid on PI3K and AMPK signaling and related transcriptional pathways that are integrated by PGC-1α, a critical regulator of energy homoestasis. The effects of lipoic acid on the neuronal energy-redox axis are largely reviewed in terms of their outcomes for aging and age-related neurodegenerative diseases.

No MeSH data available.


Related in: MedlinePlus

Thiol/disulfide exchange as the basis for the activation/inhibition of cell signaling and transcription.
© Copyright Policy - open-access
Related In: Results  -  Collection


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Figure 3: Thiol/disulfide exchange as the basis for the activation/inhibition of cell signaling and transcription.

Mentions: Extensive evidence suggests that lipoic acid has potential therapeutic value in lowering glucose levels in diabetic conditions and that the intracellular redox status plays a role in the modulation of insulin action (insulin resistance). Mechanistic studies on the effects of lipoic acid on the redox status of insulin-responsive cells revealed that lipoic acid stimulated glucose uptake by affecting components of the insulin signaling pathway. The signaling networks of insulin receptors entail binding of insulin to the receptor followed by autophosphorylation of the intracellular tyrosine kinase domain of the β-subunits and activation of signaling pathways that may be considered in three sequential nodes(30) encompassing the insulin receptor substrate (IRS1/2/3/4), PI3K, and Akt (also known as PKB). PI3K/Akt activity was shown to be necessary for the translocation of glucose transporter-4 (GLUT4) from an intracellular pool to the plasma membrane.(31–33) In a comprehensive series of studies it was found that lipoic acid augmented tyrosine phosphorylation and the activity of components of insulin signaling: insulin receptor, insulin receptor substrate-1, PI3K (type I), Akt1, and p38(34,35) (Fig. 4). The authors concluded that lipoic acid stimulated glucose uptake upon translocation and regulation of the intrinsic activity of GLUT4, an effect that might be mediated by p38 MAPK.(34) (Akt phosphorylates 160 kDa AS160, facilitating its dissociation from the GLUT4 storage vesicle and preventing inactivation of Rab-GTP). R-α-lipoic acid and oxidized isoforms are effective in stimulating glucose transport in differentiated 3T3-L1 adipocytes by a mechanism entailing changes in the intracellular redox status (but not changes in the GSH levels); lipoic acid also facilitated the autophosphorylation of the insulin receptor by a mechanism that may involve oxidation of the cysteine residues in the α- and β-subunits.(19) These effects of lipoic acid are in agreement with an alteration of the thiol reactivity of redox components of the insulin pathway caused by a thiol/disulfide exchange mechanism (Fig. 3). The inhibition of protein tyrosine phosphatase 1B activity by lipoic acid was also associated with a decrease in thiol reactivity of the enzyme.(20) Lipoic acid inhibits differentiation of 3T3-L1 pre-adipocytes by activation of JNK and ERK pathways and, in turn, transcription factors,(24) a different mechanism by which lipoic acid increases glucose uptake (i.e., activation of the insulin receptor/Akt pathway).


Lipoic acid: energy metabolism and redox regulation of transcription and cell signaling.

Packer L, Cadenas E - J Clin Biochem Nutr (2010)

Thiol/disulfide exchange as the basis for the activation/inhibition of cell signaling and transcription.
© Copyright Policy - open-access
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3022059&req=5

Figure 3: Thiol/disulfide exchange as the basis for the activation/inhibition of cell signaling and transcription.
Mentions: Extensive evidence suggests that lipoic acid has potential therapeutic value in lowering glucose levels in diabetic conditions and that the intracellular redox status plays a role in the modulation of insulin action (insulin resistance). Mechanistic studies on the effects of lipoic acid on the redox status of insulin-responsive cells revealed that lipoic acid stimulated glucose uptake by affecting components of the insulin signaling pathway. The signaling networks of insulin receptors entail binding of insulin to the receptor followed by autophosphorylation of the intracellular tyrosine kinase domain of the β-subunits and activation of signaling pathways that may be considered in three sequential nodes(30) encompassing the insulin receptor substrate (IRS1/2/3/4), PI3K, and Akt (also known as PKB). PI3K/Akt activity was shown to be necessary for the translocation of glucose transporter-4 (GLUT4) from an intracellular pool to the plasma membrane.(31–33) In a comprehensive series of studies it was found that lipoic acid augmented tyrosine phosphorylation and the activity of components of insulin signaling: insulin receptor, insulin receptor substrate-1, PI3K (type I), Akt1, and p38(34,35) (Fig. 4). The authors concluded that lipoic acid stimulated glucose uptake upon translocation and regulation of the intrinsic activity of GLUT4, an effect that might be mediated by p38 MAPK.(34) (Akt phosphorylates 160 kDa AS160, facilitating its dissociation from the GLUT4 storage vesicle and preventing inactivation of Rab-GTP). R-α-lipoic acid and oxidized isoforms are effective in stimulating glucose transport in differentiated 3T3-L1 adipocytes by a mechanism entailing changes in the intracellular redox status (but not changes in the GSH levels); lipoic acid also facilitated the autophosphorylation of the insulin receptor by a mechanism that may involve oxidation of the cysteine residues in the α- and β-subunits.(19) These effects of lipoic acid are in agreement with an alteration of the thiol reactivity of redox components of the insulin pathway caused by a thiol/disulfide exchange mechanism (Fig. 3). The inhibition of protein tyrosine phosphatase 1B activity by lipoic acid was also associated with a decrease in thiol reactivity of the enzyme.(20) Lipoic acid inhibits differentiation of 3T3-L1 pre-adipocytes by activation of JNK and ERK pathways and, in turn, transcription factors,(24) a different mechanism by which lipoic acid increases glucose uptake (i.e., activation of the insulin receptor/Akt pathway).

Bottom Line: The diversity of beneficial effects of lipoic acid in a variety of tissues can be mechanistically viewed in terms of thiol/disulfide exchange reactions that modulate the environment's redox and energy status.Lipoic acid-driven thiol/disulfide exchange reactions appear critical for the modulation of proteins involved in cell signaling and transcription factors.This review emphasizes the effects of lipoic acid on PI3K and AMPK signaling and related transcriptional pathways that are integrated by PGC-1α, a critical regulator of energy homoestasis.

View Article: PubMed Central - PubMed

Affiliation: Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, CA 90089, USA.

ABSTRACT
The role of R-α-lipoic acid as a cofactor (lipoyllysine) in mitochondrial energy metabolism is well established. Lipoic acid non-covalently bound and exogenously administered to cells or supplemented in the diet is a potent modulator of the cell's redox status. The diversity of beneficial effects of lipoic acid in a variety of tissues can be mechanistically viewed in terms of thiol/disulfide exchange reactions that modulate the environment's redox and energy status. Lipoic acid-driven thiol/disulfide exchange reactions appear critical for the modulation of proteins involved in cell signaling and transcription factors. This review emphasizes the effects of lipoic acid on PI3K and AMPK signaling and related transcriptional pathways that are integrated by PGC-1α, a critical regulator of energy homoestasis. The effects of lipoic acid on the neuronal energy-redox axis are largely reviewed in terms of their outcomes for aging and age-related neurodegenerative diseases.

No MeSH data available.


Related in: MedlinePlus