TFE3 transcriptionally activates hepatic IRS-2, participates in insulin signaling and ameliorates diabetes.
Using an expression cloning strategy, we have identified TFE3, a basic helix-loop-helix protein, as a transactivator of metabolic genes that are regulated through an E-box in their promoters. Adenovirus-mediated expression of TFE3 in hepatocytes in culture and in vivo strongly activated expression of IRS-2 and Akt and enhanced phosphorylation of insulin-signaling kinases such as Akt, glycogen synthase kinase 3beta and p70S6 kinase. TFE3 also induced hexokinase II (HK2) and insulin-induced gene 1 (INSIG1). These changes led to metabolic consequences, such as activation of glycogen and protein synthesis, but not lipogenesis, in liver. Collectively, plasma glucose levels were markedly reduced both in normal mice and in different mouse models of diabetes, including streptozotocin-treated, db/db and KK mice. Promoter analyses showed that IRS2, HK2 and INSIG1 are direct targets of TFE3. Activation of insulin signals in both insulin depletion and resistance suggests that TFE3 could be a therapeutic target for diabetes.
Nakagawa
Yoshimi
Y
Department of Internal Medicine, Metabolism and Endocrinology, Graduate School of Comprehensive Human Sciences, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki, Japan, 305-8575.
Shimano
Hitoshi
H
Yoshikawa
Tomohiro
T
Ide
Tomohiro
T
Tamura
Mariko
M
Furusawa
Mika
M
Yamamoto
Takashi
T
Inoue
Noriyuki
N
Matsuzaka
Takashi
T
Takahashi
Akimitsu
A
Hasty
Alyssa H
AH
Suzuki
Hiroaki
H
Sone
Hirohito
H
Toyoshima
Hideo
H
Yahagi
Naoya
N
Yamada
Nobuhiro
N
D000256:Adenoviridae / Q000235:genetics / Q000378:metabolism; D000818:Animals; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / Q000378:metabolism / Q000502:physiology*; D001786:Blood Glucose / Q000378:metabolism; D015152:Blotting, Northern; D002478:Cells, Cultured; D047369:Chromatin Immunoprecipitation; D003001:Cloning, Molecular; D003920:Diabetes Mellitus / Q000628:therapy*; D003921:Diabetes Mellitus, Experimental; D004305:Dose-Response Relationship, Drug; D006003:Glycogen / Q000378:metabolism; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D049452:Green Fluorescent Proteins / Q000378:metabolism; D022781:Hepatocytes / Q000378:metabolism; D006593:Hexokinase / Q000378:metabolism; D006801:Humans; D015151:Immunoblotting; D047468:Immunoprecipitation; D007328:Insulin / Q000378:metabolism*; D055504:Insulin Receptor Substrate Proteins; D047908:Intracellular Signaling Peptides and Proteins; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008954:Models, Biological; D010750:Phosphoproteins / Q000378:metabolism*; D010766:Phosphorylation; D010957:Plasmids / Q000378:metabolism; D011401:Promoter Regions, Genetic; D017434:Protein Structure, Tertiary; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051381:Rats; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000378:metabolism; D015398:Signal Transduction; D013311:Streptozocin / Q000494:pharmacology; D013997:Time Factors; D015533:Transcriptional Activation
D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D001786:Blood Glucose; C108626:INSIG1 protein, human; C526297:IRS2 protein, human; D007328:Insulin; D055504:Insulin Receptor Substrate Proteins; D047908:Intracellular Signaling Peptides and Proteins; C526298:Irs2 protein, mouse; C526299:Irs2 protein, rat; D008565:Membrane Proteins; D010750:Phosphoproteins; C069203:TFE3 protein, human; D049452:Green Fluorescent Proteins; D013311:Streptozocin; D006003:Glycogen; D006593:Hexokinase; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; C000605508:Gsk3b protein, rat; D051057:Proto-Oncogene Proteins c-akt; D038762:Ribosomal Protein S6 Kinases, 70-kDa; D038362:Glycogen Synthase Kinase 3