Effect of R(+)α-Lipoic Acid on Pyruvate Metabolism and Fatty Acid Oxidation in Rat Hepatocytes

Jennie L. Walgren, Zainab Amani, Jo Ellyn M. McMillan, Mathias Locher, Maria G. Buse

Research output: Contribution to journalArticle

21 Citations (Scopus)

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 languageEnglish (US)
Pages (from-to)165-173
Number of pages9
JournalMetabolism: Clinical and Experimental
Volume53
Issue number2
DOIs
StatePublished - Feb 2004

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Thioctic Acid
Pyruvic Acid
Nonesterified Fatty Acids
Hepatocytes
Fatty Acids
Pyruvate Dehydrogenase Complex
Type 2 Diabetes Mellitus
Keto Acids
Glucose
Decarboxylation
Gluconeogenesis
Diabetic Neuropathies
Palmitates
Serum-Free Culture Media
Skeletal Muscle Fibers
Albumins
Skeletal Muscle
Homeostasis
Therapeutics
Cell Culture Techniques

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 journalArticle

Walgren, Jennie L. ; Amani, Zainab ; McMillan, Jo Ellyn M. ; Locher, Mathias ; Buse, Maria G. / Effect of R(+)α-Lipoic Acid on Pyruvate Metabolism and Fatty Acid Oxidation in Rat Hepatocytes. In: Metabolism: Clinical and Experimental. 2004 ; Vol. 53, No. 2. pp. 165-173.
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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.

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