Inhibition of hepatic Niemann-Pick C1-like 1 improves hepatic insulin resistance.
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.
Nomura
Mitsunori
M
Life Science and Bioethics Research Center, Tokyo Medical and Dental University, 1-5-45, Yushima D9, Bunkyo-ku, Tokyo, 113-8510 Japan.
Ishii
Hideto
H
Kawakami
Akio
A
Yoshida
Masayuki
M
D000818:Animals; D000924:Anticholesteremic Agents / Q000494:pharmacology*; D001384:Azetidines / Q000494:pharmacology*; D015153:Blotting, Western; D002478:Cells, Cultured; D002784:Cholesterol / Q000378:metabolism; D017931:DNA Primers; D004721:Endoplasmic Reticulum / Q000187:drug effects / Q000378:metabolism; D000069438:Ezetimibe; D005234:Fatty Liver / Q000378:metabolism; D005947:Glucose / Q000378:metabolism; D005951:Glucose Tolerance Test; D006801:Humans; D007333:Insulin Resistance / Q000502:physiology*; D050356:Lipid Metabolism / Q000187:drug effects; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D026901:Membrane Transport Proteins / Q000502:physiology*; D019289:Pyruvic Acid / Q000378:metabolism; D034622:RNA Interference; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D017382:Reactive Oxygen Species; D060888:Real-Time Polymerase Chain Reaction; D013481:Superoxides / Q000378:metabolism; D014280:Triglycerides / Q000378:metabolism
D000924:Anticholesteremic Agents; D001384:Azetidines; D017931:DNA Primers; D026901:Membrane Transport Proteins; C482444:NPC1L1 protein, rat; D012333:RNA, Messenger; D017382:Reactive Oxygen Species; D014280:Triglycerides; D013481:Superoxides; D019289:Pyruvic Acid; D002784:Cholesterol; D000069438:Ezetimibe; D005947:Glucose