Life Science and Bioethics Research Center, Tokyo Medical and Dental University, 1-5-45, Yushima D9, Bunkyo-ku, Tokyo, 113-8510 Japan.
Am J Physiol Endocrinol Metab. 2009 Nov;297(5):E1030-8. doi: 10.1152/ajpendo.00343.2009. Epub 2009 Aug 4.
The present study attempted to define the role of hepatic Niemann-Pick C1-like 1 (NPC1L1), a cholesterol transporter, in hepatic insulin resistance as well as hepatic steatosis. The inhibition of NPC1L1 and its molecular consequences were examined in Zucker obese fatty (ZOF) rats and cultured steatotic hepatocytes using ezetimibe, a pharmacoloigcal inhibitor of NPC1L1, and short hairpin RNA (shRNA) of NPC1L1. Ezetimibe improved hepatic insulin signaling as well as hepatic steatosis in ZOF rats. It also restored insulin sensitivity in steatotic hepatocytes in vitro through a reduction in hepatic reactive oxygen species (ROS) generation, JNK activation, and ER stress. In addition, ezetimibe recovered insulin-induced Akt activation and reduced gluconeogenic genes in the liver of ZOF rats and cultured steatotic hepatocytes. Transfection of NPC1L1 shRNA into hepatocytes also reduced ROS generation and ER stress. These results indicate that NPC1L1 contributes to hepatic insulin resistance through cholesterol accumulation, and its inhibition could be a potential therapeutic target of hepatic insulin resistance.
本研究旨在探讨肝 Niemann-Pick C1 样 1（NPC1L1）作为胆固醇转运蛋白在肝胰岛素抵抗和肝脂肪变性中的作用。使用 NPC1L1 的药理学抑制剂依折麦布和 NPC1L1 的短发夹 RNA（shRNA），在 Zucker 肥胖型（ZOF）大鼠和培养的脂肪变性肝细胞中研究 NPC1L1 的抑制作用及其分子后果。依折麦布改善了 ZOF 大鼠的肝胰岛素信号传递和肝脂肪变性。它还通过减少肝活性氧（ROS）生成、JNK 激活和内质网应激，恢复了体外脂肪变性肝细胞的胰岛素敏感性。此外，依折麦布恢复了 ZOF 大鼠和培养的脂肪变性肝细胞中胰岛素诱导的 Akt 激活，并降低了肝脏中糖异生基因的表达。NPC1L1 shRNA 转染入肝细胞也减少了 ROS 生成和内质网应激。这些结果表明，NPC1L1 通过胆固醇积累导致肝胰岛素抵抗，其抑制可能是肝胰岛素抵抗的潜在治疗靶点。
