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Hepatic Monoacylglycerol O-acyltransferase 1 as a Promising Therapeutic Target for Steatosis, Obesity, and Type 2 Diabetes

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Title: Hepatic Monoacylglycerol O-acyltransferase 1 as a Promising Therapeutic Target for Steatosis, Obesity, and Type 2 Diabetes
Authors: Hayashi, Yasuhiro Browse this author →KAKEN DB
Suemitsu, Erina Browse this author
Kajimoto, Kazuaki Browse this author →KAKEN DB
Sato, Yusuke Browse this author
Akhter, Afsana Browse this author
Sakurai, Yu Browse this author
Hatakeyama, Hiroto Browse this author →KAKEN DB
Hyodo, Mamoru Browse this author →KAKEN DB
Kaji, Noritada Browse this author →KAKEN DB
Baba, Yoshinobu Browse this author →KAKEN DB
Harashima, Hideyoshi Browse this author →KAKEN DB
Keywords: in vivo siRNA delivery
monoacylglycerol O-acyltransferase 1 (Mogat1)
type 2 diabetes
Issue Date: 18-Mar-2014
Publisher: Nature Publishing Group
Journal Title: Molecular Therapy - Nucleic Acids
Volume: 3
Start Page: e154
Publisher DOI: 10.1038/mtna.2014.4
Abstract: 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.
Type: article
Appears in Collections:薬学研究院 (Faculty of Pharmaceutical Sciences) > 雑誌発表論文等 (Peer-reviewed Journal Articles, etc)

Submitter: 梶本 和昭

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