Transcriptional activation of low-density lipoprotein receptor gene by DJ-1 and effect of DJ-1 on cholesterol homeostasis.
DJ-1 is a novel oncogene and also causative gene for familial Parkinson's disease park7. DJ-1 has multiple functions that include transcriptional regulation, anti-oxidative reaction and chaperone and mitochondrial regulation. For transcriptional regulation, DJ-1 acts as a coactivator that binds to various transcription factors, resulting in stimulation or repression of the expression of their target genes. In this study, we found the low-density lipoprotein receptor (LDLR) gene is a transcriptional target gene for DJ-1. Reduced expression of LDLR mRNA and protein was observed in DJ-1-knockdown cells and DJ-1-knockout mice and this occurred at the transcription level. Reporter gene assays using various deletion and point mutations of the LDLR promoter showed that DJ-1 stimulated promoter activity by binding to the sterol regulatory element (SRE) with sterol regulatory element binding protein (SREBP) and that stimulating activity of DJ-1 toward LDLR promoter activity was enhanced by oxidation of DJ-1. Chromatin immunoprecipitation, gel-mobility shift and co-immunoprecipitation assays showed that DJ-1 made a complex with SREBP on the SRE. Furthermore, it was found that serum LDL cholesterol level was increased in DJ-1-knockout male, but not female, mice and that the increased serum LDL cholesterol level in DJ-1-knockout male mice was cancelled by administration with estrogen, suggesting that estrogen compensates the increased level of serum LDL cholesterol in DJ-1-knockout female mice. This is the first report that DJ-1 participates in metabolism of fatty acid synthesis through transcriptional regulation of the LDLR gene.
Graduate School of Pharmaceutical Sciences, Hokkaido University, Sapporo, Japan.
Shiori
S
Yamaguchi
Takuya
T
Yamane
Kazuko
K
Takahashi-Niki
Izumi
I
Kato
Takeshi
T
Niki
Matthew S
MS
Goldberg
Jie
J
Shen
Kenji
K
Ishimoto
Takefumi
T
Doi
Sanae M M
SM
Iguchi-Ariga
Hiroyoshi
H
Ariga
D000818:Animals; D001483:Base Sequence; D002784:Cholesterol / Q000097:blood / Q000378:metabolism*; D008078:Cholesterol, LDL / Q000097:blood / Q000378:metabolism; D005260:Female; D055785:Gene Knockdown Techniques; D006706:Homeostasis / Q000235:genetics*; D006801:Humans; D008297:Male; D051379:Mice; D041681:NIH 3T3 Cells; D015513:Oncogene Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D054464:Peroxiredoxins; D011401:Promoter Regions, Genetic / Q000235:genetics; D000071617:Protein Deglycase DJ-1; D011973:Receptors, LDL / Q000172:deficiency / Q000235:genetics*; D051779:Sterol Regulatory Element Binding Proteins / Q000378:metabolism; D015533:Transcriptional Activation
D008078:Cholesterol, LDL; D015513:Oncogene Proteins; D011973:Receptors, LDL; D051779:Sterol Regulatory Element Binding Proteins; D002784:Cholesterol; D054464:Peroxiredoxins; C503466:PARK7 protein, mouse; D000071617:Protein Deglycase DJ-1