The Roles of Carbohydrate Response Element Binding Protein in the Relationship between Carbohydrate Intake and Diseases

Abstract

Carbohydrates are macronutrients that serve as energy sources. Many studies have shown that carbohydrate intake is nonlinearly associated with mortality. Moreover, high-fructose corn syrup (HFCS) consumption is positively associated with obesity, cardiovascular disease, and type 2 diabetes mellitus (T2DM). Accordingly, products with equal amounts of glucose and fructose have the worst effects on caloric intake, body weight gain, and glucose intolerance, suggesting that carbohydrate amount, kind, and form determine mortality. Understanding the role of carbohydrate response element binding protein (ChREBP) in glucose and lipid metabolism will be beneficial for elucidating the harmful effects of high-fructose corn syrup (HFCS), as this glucose-activated transcription factor regulates glycolytic and lipogenic gene expression. Glucose and fructose coordinately supply the metabolites necessary for ChREBP activation and de novo lipogenesis. Chrebp overexpression causes fatty liver and lower plasma glucose levels, and ChREBP deletion prevents obesity and fatty liver. Intestinal ChREBP regulates fructose absorption and catabolism, and adipose-specific Chrebp-knockout mice show insulin resistance. ChREBP also regulates the appetite for sweets by controlling fibroblast growth factor 21, which promotes energy expenditure. Thus, ChREBP partly mimics the effects of carbohydrate, especially HFCS. The relationship between carbohydrate intake and diseases partly resembles those between ChREBP activity and diseases.

Keywords: ChREBP; HFCS; SSBs; T2DM; carbohydrate response element binding protein; fructose; glucose; high-fructose corn syrup; sugar-sweetened beverages; type 2 diabetes mellitus.

Figure 1

The association between carbohydrate type and mortality.

Figure 2

Glucose activates ChREBP, which then promotes fructolysis. Glucose increases the levels of metabolites that activate ChREBP. Upon activation, ChREBP induces fructolytic and lipogenic gene expression.

Figure 3

High-fructose corn syrup and ChREBP.

Figure 4

Merit and demerit of modulating ChREBP activity.45.

Figure 5

Carbohydrate intake and ChREBP activity, metabolic syndrome, and mortality. Sugars potently activate, starch modestly activates, and dietary fiber probably weakly activates ChREBP. The relationship between carbohydrate intake and ChREBP activity is similar to those of metabolic syndrome (hyperglycemia, hyperlipidemia, obesity, and fatty liver) and mortality. ? implies that its effect is not yet evaluated or probably lower.