Abstract
Carbohydrate response element binding protein (ChREBP) is a lipogenic transcription factor that is thought to be involved in the development of hepatic steatosis and insulin resistance. Increased ChREBP expression in liver results in increased hepatic steatosis, and the isoform ChREBPβ in adipose tissue can predict insulin sensitivity in obese humans. As ChREBP is activated by glucose, it was postulated that the composition of diet would regulate ChREBP isoform expression in metabolically relevant tissues.We compared the effects of diets with high complex carbohydrate, high fat, or a normal chow on ChREBP expression and metabolic parameters in C57BL/6 mice. We found that diets high in fat decrease ChREBP expression in adipose tissue, but isocaloric diets high in carbohydrate have no effect. Interestingly, this decrease in adipose ChREBP was associated with increased inflammatory markers. In the same animals a high carbohydrate diet induced a robust increase in hepatic ChREBPβ expression (≈2-fold; p = 0.0002), but little detectable change in the more abundant ChREBPα transcript. This change was accompanied by increased expression of target genes liver pyruvate kinase (p<0.0001), acetyl-CoA carboxylase (p = 0.0191) and stearoyl-CoA desaturase-1 (p = 0.0045). This increase in ChREBP expression was associated with increased hepatic steatosis, despite no changes in body weight or body fat when compared to chow-fed mice. Unexpectedly, mice fed a high carbohydrate diet displayed enhanced sensitivity to exogenous insulin, despite having mild glucose intolerance and increased liver steatosis.In summary, we have shown the composition of diet can selectively regulate ChREBP isoform expression in a tissue specific manner. Furthermore, we have shown a high complex carbohydrate diet selectively increases hepatic ChREBPβ expression, which associates with hepatic steatosis but not insulin resistance. In contrast, a high fat diet reduces adipose ChREBP, which associates with inflammation and insulin resistance.
Highlights
Carbohydrate response element binding protein (ChREBP) is a transcription factor that regulates genes involved in glycolysis, gluconeogenesis and lipogenesis [1]
We sought to determine the differential effects of a high calorie, high complex-carbohydrate diet (HCD), a high calorie, high-fat diet (HFD), and a low calorie, low-fat chow diet (Chow) on the metabolic function and ChREBP expression in C57BL/6 mice
The HCD mice displayed mild glucose intolerance and increased insulin sensitivity in comparison to glucose intolerance and insulin resistance when mice were placed on a HFD
Summary
Carbohydrate response element binding protein (ChREBP) is a transcription factor that regulates genes involved in glycolysis, gluconeogenesis and lipogenesis [1]. It has a key role in de novo lipogenesis in the liver, but is expressed in various other tissues including white adipose tissue, brown adipose tissue, small intestine, kidney, and pancreas [2,3,4,5]. ChREBP regulates liver de novo lipogenesis and there is strong evidence that it plays a leading role in the development of hepatic steatosis. Inhibition of ChREBP in the liver of ob/ob mice results in decreased lipogenesis and hepatic steatosis [19]. Considering the associations between ChREBP isoform mRNA expression and metabolic health, the transcriptional regulation of ChREBP isoforms warrants further investigation
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