The Role of Carbohydrate Response Element Binding Protein in Intestinal and Hepatic Fructose Metabolism

Abstract

Many articles have discussed the relationship between fructose consumption and the incidence of obesity and related diseases. Fructose is absorbed in the intestine and metabolized in the liver to glucose, lactate, glycogen, and, to a lesser extent, lipids. Unabsorbed fructose causes bacterial fermentation, resulting in irritable bowl syndrome. Therefore, understanding the mechanisms underlying intestinal and hepatic fructose metabolism is important for the treatment of metabolic syndrome and fructose malabsorption. Carbohydrate response element binding protein (ChREBP) is a glucose-activated transcription factor that controls approximately 50% of de novo lipogenesis in the liver. ChREBP target genes are involved in glycolysis (Glut2, liver pyruvate kinase), fructolysis (Glut5, ketohexokinase), and lipogenesis (acetyl CoA carboxylase, fatty acid synthase). ChREBP gene deletion protects against high sucrose diet-induced and leptin-deficient obesity, because Chrebp^-/- mice cannot consume fructose or sucrose. Moreover, ChREBP contributes to some of the physiological effects of fructose on sweet taste preference and glucose production through regulation of ChREBP target genes, such as fibroblast growth factor-21 and glucose-6-phosphatase catalytic subunits. Thus, ChREBP might play roles in fructose metabolism. Restriction of excess fructose intake will be beneficial for preventing not only metabolic syndrome but also irritable bowl syndrome.

Keywords: ChREBP; Glut5/SLC2A5; carbohydrate response element binding protein; fructolysis; fructose; glycolysis; ketohexokinase.

Figure 1

ChREBP regulates fructolytic gene expression. Fructose is transported by GLUT5 and metabolized by ketohexokinase, aldolase B, and triokinase. Dihydroxyacetone phosphate and glyceraldehyde-3-phosphate enter into the glycolytic or gluconeogenic pathway. * Genes are regulated by ChREBP [14,20,23,24,25]. Khk, ketohexokinase; G6pc, glucose-6-phosphatase catalytic subunit; Aldb, aldolase B; Pklr, pyruvate kinase, liver and reticulocyte type; Acc, acetyl coA carboxylase; Fasn, fatty acid synthase; Tkfc, triokinase; ChREBP, carbohydrate response element binding protein; GLUT2, glucose transporter 2; GLUT5, glucose transporter 5; DHAP, Dihydroxyacetone phosphate; ATP, adenosine triphosphate; ADP, adenosine diphosphate; AMP, adenosine monophosphate.

Figure 2

Metabolic fate of fructose. Fructose is slowly absorbed in the intestine. If excess fructose is consumed, unabsorbed fructose causes bacterial fermentation and, thereby, irritable bowel syndrome. Absorbed fructose is converted into glucose (50%), glycogen (~17%), lactate (25%), and triacylglycerol (TAG) (1%) [11].

Figure 3

ChREBP transactivities are regulated by several factors. ChREBP is activated by glucose derived metabolites and suppressed by AMP, ketone bodies and cyclic cAMP [43,44,45,46,47,48,49,50,51,52]. AMP, adenosine monophosphate; AMPK, AMP-activated protein kinase; cAMP, cyclic AMP.

Figure 4

ChREBP has an important role in regulating glucose and lipid metabolism. Glucose and fructose regulate many genes expression through ChREBP activation [14,20,23,24,25]. Glut2, glucose transporter 2; Glut4, glucose transporter 4; Pklr, pyruvate kinase, liver and red blood cell; Glut5, glucose transporter 5; Khk, ketohexokinase; Fasn, fatty acid synthase; Acc1, acetyl coA carboxylase 1; Scd1, stearoyl CoA desaturase; G6pc, glucose-6-phosphatase catalytic subunit; Fbp1, fructose-1,6-bisphosphatase 1; G6pdh, hexose-6-phosphate dehydrogenase; Tkt, transketolase; Mttp, microsomal triglyceride transfer protein; Klf10, kruppel-like factor 10; Klf15, kruppel-like factor 15; BHLHE40, basic helix-loop-helix family, member E40; Bhlhb2, Basic helix-loop-helix domain-containing protein, class B; Hnf1a, hepatocyte nuclear factor 1a; Hif1, hypoxia inducible factor 1; Fgf21, fibroblast growth factor 21; Angptl8, angiopoietin like 8; Gcgr, glucagon receptor; Adipor2, adiponectin receptor 2.

Figure 5

Fructose induces G6pc and Fgf21 gene expression thorugh ChREBP activation. ChREBP-α regulates ChREBP target genes expression. In turn, products of ChREBP target genes (ChREBP-β, G6pc, Gcgr, and Fgf-21) might suppress ChREBP transactivity [20,21,22,67,73]. FGF-21 suppress ChREBP transactivity by decreasing sweets intake [70,71]. GCGR might suppress ChREBP activity by enhancing glucagon effects and thereby protein kinase A activity. G6PC might suppress ChREBP activity by decreasing intracellular G6P levels. G6PC, glucose-6-phosphatase catalytic subunit; GCGR, glucagon receptor; FGF21, fibroblast growth factor-21; G6P, glucose -6-phosphate; ChREBP, carbohydrate response element binding protein.