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

Research output: Contribution to journalArticle

30 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)e154
JournalMolecular Therapy - Nucleic Acids
Volume3
DOIs
Publication statusPublished - Jan 1 2014
Externally publishedYes

Fingerprint

Type 2 Diabetes Mellitus
Obesity
Liver
Small Interfering RNA
Metabolic Diseases
Therapeutics
Obese Mice
2-acylglycerol O-acyltransferase
Genetic Association Studies
Gene Expression Profiling
Drug Discovery
Knockout Mice
Disease Progression
Blood Glucose
Triglycerides
Up-Regulation
Diet
Technology
Enzymes
Genes

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Drug Discovery

Cite this

Hepatic monoacylglycerol O-acyltransferase 1 as a promising therapeutic target for steatosis, obesity, and type 2 diabetes. / Hayashi, Yasuhiro; Suemitsu, Erina; Kajimoto, Kazuaki; Sato, Yusuke; Akhter, Afsana; Sakurai, Yu; Hatakeyama, Hiroto; Hyodo, Mamoru; Kaji, Noritada; Baba, Yoshinobu; Harashima, Hideyoshi.

In: Molecular Therapy - Nucleic Acids, Vol. 3, 01.01.2014, p. e154.

Research output: Contribution to journalArticle

Hayashi, Y, Suemitsu, E, Kajimoto, K, Sato, Y, Akhter, A, Sakurai, Y, Hatakeyama, H, Hyodo, M, Kaji, N, Baba, Y & Harashima, H 2014, 'Hepatic monoacylglycerol O-acyltransferase 1 as a promising therapeutic target for steatosis, obesity, and type 2 diabetes', Molecular Therapy - Nucleic Acids, vol. 3, pp. e154. https://doi.org/10.1038/mtna.2014.4
Hayashi, Yasuhiro ; Suemitsu, Erina ; Kajimoto, Kazuaki ; Sato, Yusuke ; Akhter, Afsana ; Sakurai, Yu ; Hatakeyama, Hiroto ; Hyodo, Mamoru ; Kaji, Noritada ; Baba, Yoshinobu ; Harashima, Hideyoshi. / Hepatic monoacylglycerol O-acyltransferase 1 as a promising therapeutic target for steatosis, obesity, and type 2 diabetes. In: Molecular Therapy - Nucleic Acids. 2014 ; Vol. 3. pp. e154.
@article{28868b1d04d44bb8a4b9e24626e5e31e,
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.",
author = "Yasuhiro Hayashi and Erina Suemitsu and Kazuaki Kajimoto and Yusuke Sato and Afsana Akhter and Yu Sakurai and Hiroto Hatakeyama and Mamoru Hyodo and Noritada Kaji and Yoshinobu Baba and Hideyoshi Harashima",
year = "2014",
month = "1",
day = "1",
doi = "10.1038/mtna.2014.4",
language = "English",
volume = "3",
pages = "e154",
journal = "Molecular Therapy - Nucleic Acids",
issn = "2162-2531",
publisher = "Nature Publishing Group",

}

TY - JOUR

T1 - Hepatic monoacylglycerol O-acyltransferase 1 as a promising therapeutic target for steatosis, obesity, and type 2 diabetes

AU - Hayashi, Yasuhiro

AU - Suemitsu, Erina

AU - Kajimoto, Kazuaki

AU - Sato, Yusuke

AU - Akhter, Afsana

AU - Sakurai, Yu

AU - Hatakeyama, Hiroto

AU - Hyodo, Mamoru

AU - Kaji, Noritada

AU - Baba, Yoshinobu

AU - Harashima, Hideyoshi

PY - 2014/1/1

Y1 - 2014/1/1

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=84908108811&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84908108811&partnerID=8YFLogxK

U2 - 10.1038/mtna.2014.4

DO - 10.1038/mtna.2014.4

M3 - Article

VL - 3

SP - e154

JO - Molecular Therapy - Nucleic Acids

JF - Molecular Therapy - Nucleic Acids

SN - 2162-2531

ER -