Abstract
R-(+)-α-lipoic acid (R-LA) is the naturally occuring enantiomer of LA. It is a strong antioxidant and cofactor of key metabolic enzyme complexes catalyzing the decarboxylation of α-keto acids. Racemic LA (rac-LA) has shown promise in treating diabetic polyneuropathy, and some studies suggest that it improves glucose homeostasis in patients with type 2 diabetes. We examined the effects of R-LA on pyruvate metabolism and free fatty acid (FFA) oxidation in primary cultured hepatocytes isolated from 24-hour fasted rats. After overnight culture in serum-free medium, cells were pre-exposed to R-LA for 3 hours before assays. R-LA (25 to 200 μmol/L) significantly increased pyruvate oxidation (∼2-fold at the highest dose tested) measured as 14CO2 production from [1-14C] pyruvate by the cells over 1 hour post-treatment. These effects correlated with proportional, significant increases in the activation state of the pyruvate dehydrogenase (PDH) complex. R-LA treatment inhibited glucose production from pyruvate by approximately 50% at 50% at 50 μmol/L R-LA and approximately 90% at 200 μmol/L. Palmitate oxidation was measured in hepatocytes cultured in the presence of albumin and physiological (0.1 mmol/L) or high (1.5 mmol/L) concentrations of FFA. The latter markedly enhanced FFA oxidation. R-LA treatment significantly inhibited FFA oxidation in both media, but was more effective in high FFA, where it reduced FFA oxidation by 48% to 82% at 25 to 200 μmol/L, respectively. Identical doses of R-LA did not affect FFA oxidation by L6 myotubes (a cell culture model for skeletal muscle) in either high or low FFA medium, but enhanced pyruvate oxidation. In conclusion, 3-hour exposure of primary cultured rat hepatocytes to R-LA at therapeutically relevant concentrations increased pyruvate oxidation, apparently by activation of the PDH complex, and decreased gluconeogenesis and FFA oxidation. These features may prove useful in the control of type 2 diabetes.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 165-173 |
| Number of pages | 9 |
| Journal | Metabolism: Clinical and Experimental |
| Volume | 53 |
| Issue number | 2 |
| DOIs | |
| State | Published - Feb 2004 |
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ASJC Scopus subject areas
- Endocrinology, Diabetes and Metabolism
- Endocrinology
Cite this
Effect of R(+)α-Lipoic Acid on Pyruvate Metabolism and Fatty Acid Oxidation in Rat Hepatocytes. / Walgren, Jennie L.; Amani, Zainab; McMillan, Jo Ellyn M.; Locher, Mathias; Buse, Maria G.
In: Metabolism: Clinical and Experimental, Vol. 53, No. 2, 02.2004, p. 165-173.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Effect of R(+)α-Lipoic Acid on Pyruvate Metabolism and Fatty Acid Oxidation in Rat Hepatocytes
AU - Walgren, Jennie L.
AU - Amani, Zainab
AU - McMillan, Jo Ellyn M.
AU - Locher, Mathias
AU - Buse, Maria G.
PY - 2004/2
Y1 - 2004/2
N2 - R-(+)-α-lipoic acid (R-LA) is the naturally occuring enantiomer of LA. It is a strong antioxidant and cofactor of key metabolic enzyme complexes catalyzing the decarboxylation of α-keto acids. Racemic LA (rac-LA) has shown promise in treating diabetic polyneuropathy, and some studies suggest that it improves glucose homeostasis in patients with type 2 diabetes. We examined the effects of R-LA on pyruvate metabolism and free fatty acid (FFA) oxidation in primary cultured hepatocytes isolated from 24-hour fasted rats. After overnight culture in serum-free medium, cells were pre-exposed to R-LA for 3 hours before assays. R-LA (25 to 200 μmol/L) significantly increased pyruvate oxidation (∼2-fold at the highest dose tested) measured as 14CO2 production from [1-14C] pyruvate by the cells over 1 hour post-treatment. These effects correlated with proportional, significant increases in the activation state of the pyruvate dehydrogenase (PDH) complex. R-LA treatment inhibited glucose production from pyruvate by approximately 50% at 50% at 50 μmol/L R-LA and approximately 90% at 200 μmol/L. Palmitate oxidation was measured in hepatocytes cultured in the presence of albumin and physiological (0.1 mmol/L) or high (1.5 mmol/L) concentrations of FFA. The latter markedly enhanced FFA oxidation. R-LA treatment significantly inhibited FFA oxidation in both media, but was more effective in high FFA, where it reduced FFA oxidation by 48% to 82% at 25 to 200 μmol/L, respectively. Identical doses of R-LA did not affect FFA oxidation by L6 myotubes (a cell culture model for skeletal muscle) in either high or low FFA medium, but enhanced pyruvate oxidation. In conclusion, 3-hour exposure of primary cultured rat hepatocytes to R-LA at therapeutically relevant concentrations increased pyruvate oxidation, apparently by activation of the PDH complex, and decreased gluconeogenesis and FFA oxidation. These features may prove useful in the control of type 2 diabetes.
AB - R-(+)-α-lipoic acid (R-LA) is the naturally occuring enantiomer of LA. It is a strong antioxidant and cofactor of key metabolic enzyme complexes catalyzing the decarboxylation of α-keto acids. Racemic LA (rac-LA) has shown promise in treating diabetic polyneuropathy, and some studies suggest that it improves glucose homeostasis in patients with type 2 diabetes. We examined the effects of R-LA on pyruvate metabolism and free fatty acid (FFA) oxidation in primary cultured hepatocytes isolated from 24-hour fasted rats. After overnight culture in serum-free medium, cells were pre-exposed to R-LA for 3 hours before assays. R-LA (25 to 200 μmol/L) significantly increased pyruvate oxidation (∼2-fold at the highest dose tested) measured as 14CO2 production from [1-14C] pyruvate by the cells over 1 hour post-treatment. These effects correlated with proportional, significant increases in the activation state of the pyruvate dehydrogenase (PDH) complex. R-LA treatment inhibited glucose production from pyruvate by approximately 50% at 50% at 50 μmol/L R-LA and approximately 90% at 200 μmol/L. Palmitate oxidation was measured in hepatocytes cultured in the presence of albumin and physiological (0.1 mmol/L) or high (1.5 mmol/L) concentrations of FFA. The latter markedly enhanced FFA oxidation. R-LA treatment significantly inhibited FFA oxidation in both media, but was more effective in high FFA, where it reduced FFA oxidation by 48% to 82% at 25 to 200 μmol/L, respectively. Identical doses of R-LA did not affect FFA oxidation by L6 myotubes (a cell culture model for skeletal muscle) in either high or low FFA medium, but enhanced pyruvate oxidation. In conclusion, 3-hour exposure of primary cultured rat hepatocytes to R-LA at therapeutically relevant concentrations increased pyruvate oxidation, apparently by activation of the PDH complex, and decreased gluconeogenesis and FFA oxidation. These features may prove useful in the control of type 2 diabetes.
UR - http://www.scopus.com/inward/record.url?scp=0842284605&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=0842284605&partnerID=8YFLogxK
U2 - 10.1016/j.metabol.2003.09.008
DO - 10.1016/j.metabol.2003.09.008
M3 - Article
C2 - 14767867
AN - SCOPUS:0842284605
VL - 53
SP - 165
EP - 173
JO - Metabolism: Clinical and Experimental
JF - Metabolism: Clinical and Experimental
SN - 0026-0495
IS - 2
ER -