Hepatic monoacylglycerol O-acyltransferase 1 as a promising therapeutic target for steatosis, obesity, and type 2 diabetes

Yasuhiro Hayashi, Erina Suemitsu, Kazuaki Kajimoto, Yusuke Sato, Afsana Akhter, Yu Sakurai, Hiroto Hatakeyama, Mamoru Hyodo, Noritada Kaji, Yoshinobu Baba, Hideyoshi Harashima

研究成果: Contribution to journalArticle

32 被引用数 (Scopus)

抄録

Over the past decade, considerable advances have been made in the discovery of gene targets in metabolic diseases. However, in vivo studies based on molecular biological technologies such as the generation of knockout mice and the construction of short hairpin RNA vectors require considerable effort and time, which is a major limitation for in vivo functional analysis. Here, we introduce a liver-specific nonviral small interfering RNA (siRNA) delivery system into rapid and efficient characterization of hepatic gene targets in metabolic disease mice. The comparative transcriptome analysis in liver between KKAy diabetic and normal control mice demonstrated that the expression of monoacylglycerol O-acyltransferase 1 (Mogat1), an enzyme involved in triglyceride synthesis and storage, was highly elevated during the disease progression. The upregulation of Mogat1 expression in liver was also found in other genetic (db/db) and diet-induced obese mice. The silencing of hepatic Mogat1 via a liver-specific siRNA delivery system resulted in a dramatic improvement in blood glucose levels and hepatic steatosis as well as overweight with no apparent overall toxicities, indicating that hepatic Mogat1 is a promising therapeutic target for metabolic diseases. The integrated approach with transcriptomics and nonviral siRNA delivery system provides a blueprint for rapid drug discovery and development.

本文言語英語
ページ(範囲)e154
ジャーナルMolecular Therapy - Nucleic Acids
3
DOI
出版ステータス出版済み - 2014
外部発表はい

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Drug Discovery

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