Walgren Jennie L, Amani Zainab, McMillan JoEllyn M, Locher Mathias, Buse Maria G
Department of Pharmacology, Medical University of South Carolina, Charleston, SC, USA.
Metabolism. 2004 Feb;53(2):165-73. doi: 10.1016/j.metabol.2003.09.008.
R-(+)-alpha-lipoic acid (R-LA) is the naturally occurring enantiomer of LA. It is a strong antioxidant and cofactor of key metabolic enzyme complexes catalyzing the decarboxylation of alpha-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 micromol/L) significantly increased pyruvate oxidation ( approximately 2-fold at the highest dose tested) measured as (14)CO(2) production from [1-(14)C]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 micromol/L R-LA and approximately 90% at 200 micromol/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 micromol/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.
R-(+)-α-硫辛酸（R-LA）是硫辛酸的天然对映体。它是一种强大的抗氧化剂，也是催化α-酮酸脱羧的关键代谢酶复合物的辅助因子。消旋硫辛酸（rac-LA）在治疗糖尿病性多发性神经病方面已显示出前景，一些研究表明它可改善2型糖尿病患者的葡萄糖稳态。我们研究了R-LA对从禁食24小时大鼠分离的原代培养肝细胞中丙酮酸代谢和游离脂肪酸（FFA）氧化的影响。在无血清培养基中过夜培养后，在测定前将细胞预先暴露于R-LA 3小时。R-LA（25至200微摩尔/升）显著增加了丙酮酸氧化（在测试的最高剂量下约增加2倍），以处理后1小时内细胞从[1-(14)C]丙酮酸产生的(14)CO(2)量来衡量。这些作用与丙酮酸脱氢酶（PDH）复合物激活状态的成比例显著增加相关。在50微摩尔/升R-LA时，R-LA处理抑制丙酮酸生成葡萄糖约50%，在200微摩尔/升时约抑制90%。在存在白蛋白以及生理浓度（0.1毫摩尔/升）或高浓度（1.5毫摩尔/升）FFA的情况下培养的肝细胞中测量棕榈酸氧化。后者显著增强了FFA氧化。R-LA处理在两种培养基中均显著抑制FFA氧化，但在高FFA培养基中更有效，在25至200微摩尔/升时分别将FFA氧化降低48%至82%。相同剂量的R-LA在高或低FFA培养基中均不影响L6肌管（骨骼肌细胞培养模型）的FFA氧化，但增强了丙酮酸氧化。总之，原代培养的大鼠肝细胞在治疗相关浓度下暴露于R-LA 3小时可增加丙酮酸氧化，显然是通过激活PDH复合物实现的，并减少糖异生和FFA氧化。这些特性可能在2型糖尿病的控制中证明是有用的。
