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.

Intestinal Fructose and Glucose Metabolism in Health and Disease

“…High fructose diet feeding increases intestinal ChREBP protein levels, accompanied by increased fructose transport (GLUT5), fructolytic (fructokinase, ALDOB, TKFC, and lactate dehydrogenase) and gluconeogenic (glucose-6-phosphatae and fructose-1,6-bisphosphatase) gene expression in mice [55]. Conversely, genetic ablation of ChREBP (ChREBP-KO mice) leads to fructose intolerance due to insufficient induction of these genes involved in fructose transport and metabolism [55][56][57][58][59]. The molecular mechanism by which fructose mediates ChREBP-induction of Slc2a5 gene expression involves direct interaction of ChREBP with the promoter of Slc2a5 [55] in mice, whereas ectopic co-expression of ChREBP and its heterodimer partner Max-like protein X (MLX) binds to carbohydrate response elements (ChoREs) and activates Slc2a5 promoter in Caco-2BBE human cells [55].…”

“…The molecular mechanism by which fructose mediates ChREBP-induction of Slc2a5 gene expression involves direct interaction of ChREBP with the promoter of Slc2a5 [55] in mice, whereas ectopic co-expression of ChREBP and its heterodimer partner Max-like protein X (MLX) binds to carbohydrate response elements (ChoREs) and activates Slc2a5 promoter in Caco-2BBE human cells [55]. Further work is required to confirm whether, similarly to glucose, fructose might regulate ChREBP activity by posttranslational modifications such as O-glycosylation, phosphorylation and conformational changes in intestinal cells [57].…”

GutSelf: Interindividual Variability in the Processing of Dietary Compounds by the Human Gastrointestinal Tract

“…Fructose is absorbed in the small intestine via the glucose transporter (GLUT) 5, which possesses a limited capacity of absorption, and transported into the blood by GLUT2. Fructose can be metabolized in the small intestine and liver by enzymes such as fructokinase, aldolase B, and triokinase . Carbohydrate response element‐binding protein (ChREBP) is a transcription factor involved in glycolytic and lipogenic gene expression linked to carbohydrate consumption.…”

“…Carbohydrate response element‐binding protein (ChREBP) is a transcription factor involved in glycolytic and lipogenic gene expression linked to carbohydrate consumption. ChREBP target genes are implicated in fructolysis (Glut5, fructokinase), glycolysis (Glut2, liver pyruvate kinase), and lipogenesis (acetyl CoA carboxylase, fatty acid synthase) …”

A Sweet Connection? Fructose’s Role in Hepatocellular Carcinoma

“…Fructose has been shown to increase the activity of proteins involved in lipogenesis, gluconeogenesis, and glycolysis. Transcription factors carbohydrate-responsive element-binding protein (ChREBP) and sterol regulatory element binding protein-1 (SREBP-1) are potent inducers of lipogenesis by activating genes such as fatty acid synthase (FAS) and acetyl coA carboxylase (ACC) [25], and have been demonstrated to have increased activity in response to fructose feeding [30][31][32][33]. Additionally, fructose increases the expression of the gluconeogenic enzymes glucose-6-phosphatase (G6Pase) and fructose 1,6-biphosphatase 1 (FBP1), the glycolytic enzymes phosphofructokinase 1 (PFK1) and pyruvate kinase (PK), and increases glycogen and hepatic glucose production [32,33].…”