Hepatic overexpression of dominant negative Mlx improves metabolic profile in diabetes-prone C57BL/6J mice.
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.
Iizuka
Katsumi
K
Laboratory of Medical Genomics, The Institute for Molecular and Cellular Regulation, Gunma University, Maebashi-shi, 371-8512, Japan.
Takeda
Jun
J
Horikawa
Yukio
Y
D000123:Acetyltransferases / Q000235:genetics; D000818:Animals; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D003920:Diabetes Mellitus / Q000378:metabolism*; D019281:Dimerization; D000081031:Fatty Acid Elongases; D064429:Fatty Acid Synthases / Q000235:genetics; D015870:Gene Expression; D018149:Glucose Intolerance / Q000378:metabolism*; D005952:Glucose-6-Phosphatase / Q000235:genetics; D022781:Hepatocytes / Q000378:metabolism; D008099:Liver / Q000378:metabolism*; D008297:Male; D024821:Metabolic Syndrome / Q000378:metabolism*; D051379:Mice; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051381:Rats; D014157:Transcription Factors / Q000037:antagonists & inhibitors* / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism
D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D004268:DNA-Binding Proteins; C000630968:Elovl6 protein, mouse; C506001:Mlxipl protein, mouse; D009687:Nuclear Proteins; C501970:Tcfl4 protein, mouse; D014157:Transcription Factors; D000123:Acetyltransferases; D000081031:Fatty Acid Elongases; D064429:Fatty Acid Synthases; D005952:Glucose-6-Phosphatase