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

-( )-lipoic acid (R-LA) is the naturally occuring enantiomer of LA. It is a strong antioxidant and cofactor of key metabolic nzyme complexes catalyzing the decarboxylation of -keto acids. Racemic LA (rac-LA) has shown promise in treating iabetic polyneuropathy, and some studies suggest that it improves glucose homeostasis in patients with type 2 diabetes. e examined the effects of R-LA on pyruvate metabolism and free fatty acid (FFA) oxidation in primary cultured hepatocytes solated from 24-hour fasted rats. After overnight culture in serum-free medium, cells were pre-exposed to R-LA for 3 hours efore assays. R-LA (25 to 200 mol/L) significantly increased pyruvate oxidation ( 2-fold at the highest dose tested) easured as CO2 production from [1C]pyruvate by the cells over 1 hour post-treatment. These effects correlated with roportional, significant increases in the activation state of the pyruvate dehydrogenase (PDH) complex. R-LA treatment nhibited glucose production from pyruvate by approximately 50% at 50 mol/L R-LA and approximately 90% at 200 mol/L. almitate 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 xidation in both media, but was more effective in high FFA, where it reduced FFA oxidation by 48% to 82% at 25 to 200 mol/L, respectively. Identical doses of R-LA did not affect FFA oxidation by L6 myotubes (a cell culture model for skeletal uscle) in either high or low FFA medium, but enhanced pyruvate oxidation. In conclusion, 3-hour exposure of primary ultured rat hepatocytes to R-LA at therapeutically relevant concentrations increased pyruvate oxidation, apparently by ctivation of the PDH complex, and decreased gluconeogenesis and FFA oxidation. These features may prove useful in the ontrol of type 2 diabetes. 2004 Elsevier Inc. All rights reserved.