阻断 L 型钙通道可改变胰岛素抵抗大鼠的肝线粒体功能

M. O. Zavhorodnii, V. Nosar, O.O. Gonchar, P. Tsapenko, M. Kozlovska, M. Vasylenko, V. Portnichenko, A. Portnychenko
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摘要

线粒体是维持能量和氧化平衡的核心细胞器。尽管研究深入,但线粒体的功能及其在生理条件下和胰岛素抵抗时的调控机制仍有待详细研究。本研究旨在探讨阻断胰岛素抵抗大鼠的 L 型钙通道对肝线粒体氧化功能及其氧化状态变化的影响。对 6 个月大的雄性 Wistar 大鼠进行为期 14 天的高脂喂养,以建立胰岛素抵抗模型。标准喂养动物作为对照组。腹腔注射维拉帕米,剂量为 1 毫克/千克,以阻断 L 型钙通道。3 小时后,在麻醉动物提取的肝脏匀浆中检测促氧化和抗氧化系统指标(刁巴比妥酸活性产物、还原型谷胱甘肽、过氧化氢酶、铜锌超氧化物歧化酶)。结果表明,在完整的动物体内,通过抑制磷酸化呼吸(V3)和刺激受控呼吸(V4),阻断 L 型钙通道会降低肝脏线粒体在氧化所有底物时的线粒体呼吸效率(V3/V4),而不会影响肝脏的氧化状态。在胰岛素抵抗的大鼠体内,依赖 NAD 和 FAD 的底物氧化过程中的 V3 速率降低,氧化状态受到破坏,抗氧化保护作用增强。然而,与对照组相比,在胰岛素抵抗大鼠体内阻断 L 型钙通道可显著增强 NAD 依赖性底物氧化过程中的基础呼吸(V2)、棕榈酰脂质底物氧化过程中的 V3 和 V4,降低 V3/V4 比率,并部分或完全恢复氧化状态的改变。这可能表明钙机制参与了胰岛素抵抗时肝脏氧化状态的紊乱和线粒体能量代谢的调节。
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Blockade of L-type calcium channels alters hepatic mitochondrial function in insulin-resistant rats
Mitochondria are central organelles in maintaining energy and oxidative homeostasis. Despite intensive research, the function of mitochondria and the mechanisms of its regulation under physiological conditions and in insulin resistance require detailed investigation. The aim of this study was to investigate the effect of blockade L-type calcium channels in insulin-resistant rats on hepatic mitochondrial oxidative function and changes in its oxidative status. Insulin resistance was modeled in 6-month-old male Wistar rats by 14 days of high-fat feeding. Standard fed animals served as controls. Verapamil was administered intraperitoneally at a dose of 1 mg/kg to block L-type calcium channels. Indicators of pro- and antioxidant systems (active products of tiobarbituric acid, reduced glutathione, catalase, Cu,Zn-superoxide dismutase) were assayed in the liver homogenate extracted from anesthetized animals after 3 h. Mitochondrial function was studied by the Chance polarographic method using different metabolic substrates. It was shown that in intact animals blockade of L-type calcium channels reduced the efficiency of mitochondrial respiration (V3/V4) in liver mitochondria during oxidation of all substrates through an inhibitory effect on the phosphorylation respiration (V3) and a stimulatory effect on the controlled respiration (V4), without affecting the oxidative status of the liver. In rats with insulin resistance the rate of V3 during oxidation of both NAD- and FADdependent substrates was decreased, violations of oxidative status and increased antioxidant protection were detected. However, in insulin-resistant rats blockade of L-type calcium channels significantly enhanced basic respiration (V2) during NAD-dependent substrate oxidation, V3 and V4 during palmitoyl lipid substrate oxidation, reduced the V3/V4 ratio compared to control, and partially or fully restored the violation of the oxidative status. This may indicate the involvement of calcium mechanisms in the disturbance of the oxidative status of the liver and the regulation of energy metabolism in mitochondria during insulin resistance.
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