[Role of increased activity of carbohydrate response element binding protein in excessive lipid accumulation in the liver of type 2 diabetic db/db mouse].
OBJECTIVE
To study the role of the carbohydrate response element binding protein (ChREBP) in excessive lipid deposition in the liver of db/db mouse.


METHODS
The deposition of neutral lipids in the liver was evaluated by Oil Red O staining. Immunohistochemical assay was utilized to determine the localization of ChREBP protein expression in mouse liver. The expressions of ChREBP and its target genes including acetyl-coenzyme A carboxylase 1 (Acc-1), fatty acid synthase (Fas), glycerol-3-phosphate acyltransferase (Gpat) were analyzed by Real-time PCR and Western blot.


RESULTS
Significant lipid droplet deposition was detected in the livers of db/db mice. ChREBP was diffusely expressed in heptocytes with relative higher expression levels around portal and central veins. ChREBP was predominantly located in the cytosol in non-diabetic db/m mice, but was translocated to the nucleus in db/db mice. Nuclear ChREBP protein levels were 8.2-fold higher in db/db mice than in db/m mice(P<0.01). In contrast, another lipogenic transcription factor, sterol regulatory element binding protein-1(SREBP-1), remained unchanged. Consistent with increased nuclear ChREBP levels, expressions of ChREBP target genes involved in lipogenesis including Acc-1, Fas and Gpat were upregulated by 2-fold(P<0.05),1.7-fold (P<0.05) and 4.2-fold(P<0.05), respectively, in db/db mice.


CONCLUSIONS
The db/db mouse exhibits significantly higher liver ChREBP activity, which may be associated with the development of hepatic steatosis frequently occurring in type 2 diabetes. Targeting ChREBP might represent a new intervention strategy for fatty liver.
Huo
Ming
M
Department of Physiology and Pathophysiology, Peking University School of Basic Medical Sciences; Key Laboratory of Molecular Cardiology, Ministry of Education; Peking University Diabetes Center, Beijing 100191, China.
Zang
Hui-ling
HL
Zhang
Dong-juan
DJ
Wang
Bing
B
Wu
Jing
J
Zhang
Xiao-yan
XY
Chen
Li-hong
LH
Li
Jing
J
Yang
Ji-chun
JC
Guan
You-fei
YF
D000818:Animals; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism*; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism*; D008055:Lipids / Q000096:biosynthesis*; D008099:Liver / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009687:Nuclear Proteins / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism*
D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D008055:Lipids; C506001:Mlxipl protein, mouse; D009687:Nuclear Proteins; D014157:Transcription Factors