title: Hepatic Monoacylglycerol O-acyltransferase 1 as a Promising Therapeutic Target for Steatosis, Obesity, and Type 2 Diabetes.
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.
authors.affiliation: Faculty of Pharmaceutical Sciences, Hokkaido University, Sapporo, Japan.
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Hayashi
authors.affiliation: Faculty of Pharmaceutical Sciences, Hokkaido University, Sapporo, Japan.
authors.forename: Erina
authors.initials: E
authors.lastname: Suemitsu
authors.affiliation: Faculty of Pharmaceutical Sciences, Hokkaido University, Sapporo, Japan.
authors.forename: Kazuaki
authors.initials: K
authors.lastname: Kajimoto
authors.affiliation: Faculty of Pharmaceutical Sciences, Hokkaido University, Sapporo, Japan.
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Sato
authors.affiliation: Faculty of Pharmaceutical Sciences, Hokkaido University, Sapporo, Japan.
authors.forename: Afsana
authors.initials: A
authors.lastname: Akhter
authors.affiliation: Faculty of Pharmaceutical Sciences, Hokkaido University, Sapporo, Japan.
authors.forename: Yu
authors.initials: Y
authors.lastname: Sakurai
authors.affiliation: Faculty of Pharmaceutical Sciences, Hokkaido University, Sapporo, Japan.
authors.forename: Hiroto
authors.initials: H
authors.lastname: Hatakeyama
authors.affiliation: Faculty of Pharmaceutical Sciences, Hokkaido University, Sapporo, Japan.
authors.forename: Mamoru
authors.initials: M
authors.lastname: Hyodo
authors.affiliation: 1] Graduate School of Engineering, Nagoya University, Nagoya, Japan [2] FIRST Research Center for Innovative Nanodevices, Nagoya University, Nagoya, Japan.
authors.forename: Noritada
authors.initials: N
authors.lastname: Kaji
authors.affiliation: 1] Graduate School of Engineering, Nagoya University, Nagoya, Japan [2] FIRST Research Center for Innovative Nanodevices, Nagoya University, Nagoya, Japan [3] Health Research Institute, National Institute of Advanced Industrial Science and Technology, Takamatsu, Japan.
authors.forename: Yoshinobu
authors.initials: Y
authors.lastname: Baba
authors.affiliation: Faculty of Pharmaceutical Sciences, Hokkaido University, Sapporo, Japan.
authors.forename: Hideyoshi
authors.initials: H
authors.lastname: Harashima