Enhancement of Liver Regeneration by Adenosine Triphosphate-Sensitive K+ Channel Opener (Diazoxide) After Partial Hepatectomy
Enhancement of Liver Regeneration by Adenosine Triphosphate-Sensitive K+ Channel Opener (Diazoxide) After Partial Hepatectomy
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DOI：
10.1097/tp.0b013e31824ef1d1
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发表时间：
2012-06-15
期刊：
影响因子：
6.2
通讯作者：
Yamamoto, Yuzo
中科院分区：
文献类型：
--
作者：
Nakagawa, Yasuhiko;Yoshioka, Masato;Yamamoto, Yuzo
背景。增强肝再生是部分肝移植（包括小型移植）后的一个重要问题。线粒体三磷酸腺苷 (ATP) 敏感的 K+ (mitoK(ATP)) 通道在线粒体生物能学中发挥重要作用，是肝脏再生的先决条件。然而，肝细胞中的 ATP 敏感性 K+ (K-ATP) 通道尚不完全清楚。我们研究了肝细胞中的 K-ATP 通道，并使用大鼠模型检查了二氮嗪（一种有效的 K-ATP 通道开放剂）对肝再生的影响。方法。使用大鼠原代肝细胞，通过聚合酶链反应、蛋白质印迹和免疫染色研究 K-ATP 通道亚基、Kir6.x 和磺酰脲受体 (SUR)x 的表达和定位。为了研究 K-ATP 通道开放剂在肝再生中的作用，我们将大鼠分为四组：对照组（媒介物）（n = 24）、二氮嗪组（n = 24）、媒介物加通道阻滞剂组（n = 6）和二氮嗪加通道阻滞剂组（n = 6）。 70%肝部分切除后，检测肝组织ATP水平、肝体重比、肝细胞增殖率。结果。在肝线粒体上检测到 K-ATP 通道亚基 Kir6.1 和 SUR1。在肝再生过程中，肝部分切除术后第2天，二氮嗪组的肝脏与体重比、肝细胞增殖率和肝脏ATP水平显着高于对照组。二氮嗪的这些作用被 K-ATP 通道阻滞剂中和。结论。我们证明了肝细胞中存在由Kir6.1和SUR1组成的mitoK(ATP)通道。二氮嗪可以通过保持肝组织较高的 ATP 含量来增强肝再生。这些结果表明二氮嗪将通过打开 mitoK(ATP) 通道来维持线粒体能量。
Background. Enhancement of liver regeneration is a matter of importance after partial liver transplantation including small-for-size grafting. Mitochondrial adenosine triphosphate (ATP)-sensitive K+ (mitoK(ATP)) channel plays an important role in mitochondrial bioenergetics, which is a prerequisite for liver regeneration. However, the ATP-sensitive K+ (K-ATP) channel in hepatocytes is incompletely understood. We investigated the K-ATP channel in hepatocytes and examined the effects of diazoxide, a potent K-ATP channel opener, on liver regeneration using a rat model.Methods. Using rat primary hepatocytes, expression and localization of K-ATP channel subunits, Kir6.x and sulfonylurea receptor (SUR)x, were studied by polymerase chain reaction, Western blotting, and immunostaining. To investigate the role of K-ATP channel openers in liver regeneration, we allocated rats into four groups: control (vehicle) (n=24), diazoxide (n=24), vehicle plus channel blocker (n=6), and diazoxide plus channel blocker (n=6) groups. After 70% partial hepatectomy, hepatic tissue ATP levels, liver-to-body weight ratio, and proliferation rate of hepatocytes were examined.Results. K-ATP channel subunits, Kir6.1 and SUR1, were detected on hepatic mitochondria. During liver regeneration, liver-to-body weight ratio, proliferation rate of hepatocytes, and the hepatic ATP level were significantly higher in the diazoxide group than the control group at 2 days after partial hepatectomy. These effects of diazoxide were neutralized by a K-ATP channel blocker.Conclusions. We demonstrated the existence of a mitoK(ATP) channel in hepatocytes composed of Kir6.1 and SUR1. Diazoxide could enhance liver regeneration by keeping a higher ATP content of the liver tissue. These results suggest that diazoxide will sustain the mitochondrial energetics through the mitoK(ATP) channel opening.