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Am J Physiol Endocrinol Metab 297: E1030-E1038, 2009. First published August 4, 2009; doi:10.1152/ajpendo.00343.2009
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Inhibition of hepatic Niemann-Pick C1-like 1 improves hepatic insulin resistance

Mitsunori Nomura,1 Hideto Ishii,1 Akio Kawakami,2 and Masayuki Yoshida1

1Life Science and Bioethics Research Center, 2Department of Vascular Medicine, Graduate School of Medicine, Tokyo Medical and Dental University, Tokyo, Japan

Submitted 26 May 2009 ; accepted in final form 30 July 2009

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.

cholesterol transporter; oxidative stress; endoplasmic reticulum stress


Address for reprint requests and other correspondence: M. Yoshida, Life Science and Bioethics Research Center, Tokyo Medical and Dental University, 1-5-45, Yushima D9, Bunkyo-ku, Tokyo, 113-8510 Japan (e-mail: masavasc{at}tmd.ac.jp).






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