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KMID : 1161520160200010007
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Animal Cells and Systems
2016 Volume.20 No. 1 p.7 ~ p.14
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Hepatic DGAT2 gene expression is regulated by the synergistic action of ChREBP and SP1 in HepG2 cells
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Shin Eun-Ji
Bae Jin-Sik
Han Jung-Youn
Lee Jung-Hoon
Jeong Yun-Seung
Lee Ho-Jae
Ahn Yong-Ho
Cha Ji-Young
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Abstract
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Diacylglycerol acyltransferase 2 (DGAT2) catalyzes the final step of triglyceride synthesis and plays a critical role in the development of fatty liver disease and insulin resistance. The expression of DGAT2 is mostly induced by dietary carbohydrate in the mammalian liver; however, the transcription factors that regulate DGAT2 expression have yet to be identified. In this study, we investigated the molecular mechanism underlying the glucose-induced transcriptional regulation of human DGAT2 in HepG2 cells. Human DGAT2 expression was increased by glucose in HepG2 cells. Transfection studies of the DGAT2 promoter-luciferase reporter construct in vitro and in silico analysis identified two glucose-responsive regions in the DGAT2 promoter. Each region contains one ChREBP/MLX (carbohydrate response element binding protein/Max-like protein) binding site (ChoRE, ?539 to ?551 and ?6067 to ?6083) and one specificity protein 1 (SP1) binding site (GC-rich motif, ?556 to ?572 and ?6016 to ?6032). Mutational analysis showed that both ChREBP/MLX and SP1 sites are required for the glucose-induced transcription of DGAT2. Gel shift assays and chromatin immunoprecipitation assays demonstrated that ChREBP and SP1 bind directly to ChoRE and the GC-rich motif, respectively. High glucose promoted the recruitment of ChREBP to ChoRE, whereas SP1 was recruited to the GC-rich motif even under low-glucose conditions. These data demonstrate that both ChREBP and SP1 are key factors to regulate the expression of human DGAT2 by glucose.
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KEYWORD
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DGAT2, ChREBP, SP1, triglyceride synthesis, transcriptional regulation
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