HDAC1/HDAC3 modulates PPARG2 transcription through the sumoylated CEBPD in hepatic lipogenesis.
CCAAT/Enhancer binding proteins (C/EBPs) and peroxisome proliferator-activated receptors gamma (PPARG) play critical roles in the regulation of lipid metabolism genes. Overexpression of CEBPdelta (CEBPD) enhances lipid accumulation and specifically activates PPARG2 transcription in HepG2 cells. By using 5'-serial deletion reporter analysis, we show that the region comprising the -457 to +129 base pairs is required for CEBPD response of the PPARG2 promoter. Two critical CEBPD-binding motifs on the -324/-311 and -158/-145 of human PPARG2 promoter are identified. We previously have shown that the human CEBPD is sumoylated by small ubiquitin-related modifier-1 (SUMO1). We further demonstrated that the sumoylation of CEBPD lysine 120 is also detectable in HepG2 cells, and this modification functions for binding of the recruits, HDAC1 and HDAC3. Meanwhile, an in vivo chromatin IP assay demonstrated that the sumoylation mutant of CEBPD lost a significant portion of HDAC1 and HDAC3 interaction. Combining that the increasing amount of CEBPD and the sumoylated CEBPD (suCEBPD) consistently responded to lipogenic stimulation, these results suggest that the excess non-sumoylated CEBPD could be a critical activator which reverses suCEBPD/HDAC1/HDAC3-mediated PPARG2 gene inactivation and promotes hepatic lipogenesis. Taken together, we suggest that suCEBPD/HDAC1/HDAC3 complex inactivates PPARG2 transcription, and the induction of CEBPD expression transiently activates PPARG2 transcription which is involved in adipocyte-like lipogenesis in HepG2 cells.
Lai
Pei-Hua
PH
Institute of Biosignal Transduction, College of Bioscience and Biotechnology, National Cheng Kung University, Tainan 70101, Taiwan.
Wang
Wen-Lin
WL
Ko
Chiung-Yuan
CY
Lee
Yi-Chao
YC
Yang
Wen-Ming
WM
Shen
Tsung-Wei
TW
Chang
Wen-Chang
WC
Wang
Ju-Ming
JM
D051743:CCAAT-Enhancer-Binding Protein-delta / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D015972:Gene Expression Regulation, Neoplastic; D056284:Histone Deacetylase 1; D006655:Histone Deacetylases / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D050155:Lipogenesis; D008099:Liver / Q000378:metabolism*; D047495:PPAR gamma / Q000235:genetics / Q000378:metabolism*; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding; D025842:SUMO-1 Protein / Q000378:metabolism*; D014158:Transcription, Genetic / Q000235:genetics; D000099186:Histone Deacetylase 3
D051743:CCAAT-Enhancer-Binding Protein-delta; D056284:Histone Deacetylase 1; D006655:Histone Deacetylases; D047495:PPAR gamma; D025842:SUMO-1 Protein; D000099186:Histone Deacetylase 3; C497252:CEBPD protein, human; C110550:HDAC1 protein, human