Role of increased activity of carbohydrate response element binding protein in excessive lipid accumulation in the liver of type 2 diabetic db/db mouse

To study the role of the carbohydrate response element binding protein (ChREBP) in excessive lipid deposition in the liver of db/db mouse.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.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.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.PubMed03307-124