Hepatic overexpression of dominant negative Mlx improves metabolic profile in diabetes-prone C57BL/6J mice

Katsumi Iizuka; Jun Takeda; Yukio Horikawa

doi:10.1016/j.bbrc.2008.12.100

Hepatic overexpression of dominant negative Mlx improves metabolic profile in diabetes-prone C57BL/6J mice

Biochem Biophys Res Commun. 2009 Feb 6;379(2):499-504. doi: 10.1016/j.bbrc.2008.12.100. Epub 2008 Dec 31.

Authors

Katsumi Iizuka¹, Jun Takeda, Yukio Horikawa

Affiliation

¹ Laboratory of Medical Genomics, The Institute for Molecular and Cellular Regulation, Gunma University, Maebashi-shi, 371-8512, Japan.

PMID: 19121288
DOI: 10.1016/j.bbrc.2008.12.100

Abstract

Mlx and ChREBP form a heterodimer to regulate glucose-mediated gene expression in the liver. This study was performed to determine if the metabolic syndrome might be improved using dominant negative Mlx (dnMlx). An adenovirus bearing dnMlx was constructed and used to test the inhibitory effect of dnMlx on lipogenesis both in vitro and in vivo. Adenoviral overexpression of dnMlx in rat hepatocytes inhibited expression of glucose-regulated genes, including Chrebp and Transketolase, which constitute a positive feedback loop in the regulation of Chrebp gene expression. Adenoviral overexpression of dnMlx in 25-week-old male C57BL/6J mice reduced hepatic triglyceride contents and improved glucose intolerance by inhibiting expression of Glucose-6-phosphatase and Elovl6 mRNA in addition to lipogenic enzymes. In conclusion, overexpression of dnMlx improves glucose intolerance by inhibiting expression not only of lipogenic enzymes but also other important genes such as Glucose-6-phosphatase and Elovl6.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Acetyltransferases / genetics
Animals
Basic Helix-Loop-Helix Leucine Zipper Transcription Factors
Cells, Cultured
DNA-Binding Proteins / biosynthesis*
DNA-Binding Proteins / genetics
DNA-Binding Proteins / metabolism
Diabetes Mellitus / metabolism*
Dimerization
Fatty Acid Elongases
Fatty Acid Synthases / genetics
Gene Expression
Glucose Intolerance / metabolism*
Glucose-6-Phosphatase / genetics
Hepatocytes / metabolism
Liver / metabolism*
Male
Metabolic Syndrome / metabolism*
Mice
Nuclear Proteins / antagonists & inhibitors*
Nuclear Proteins / metabolism
Rats
Transcription Factors / antagonists & inhibitors*
Transcription Factors / biosynthesis*
Transcription Factors / genetics
Transcription Factors / metabolism

Substances

Basic Helix-Loop-Helix Leucine Zipper Transcription Factors
DNA-Binding Proteins
Elovl6 protein, mouse
Mlxipl protein, mouse
Nuclear Proteins
Tcfl4 protein, mouse
Transcription Factors
Acetyltransferases
Fatty Acid Elongases
Fatty Acid Synthases
Glucose-6-Phosphatase