Dietary Fructose and the Metabolic Syndrome

Abstract

Abstract: Consumption of fructose, the sweetest of all naturally occurring carbohydrates, has increased dramatically in the last 40 years and is today commonly used commercially in soft drinks, juice, and baked goods. These products comprise a large proportion of the modern diet, in particular in children, adolescents, and young adults. A large body of evidence associate consumption of fructose and other sugar-sweetened beverages with insulin resistance, intrahepatic lipid accumulation, and hypertriglyceridemia. In the long term, these risk factors may contribute to the development of type 2 diabetes and cardiovascular diseases. Fructose is absorbed in the small intestine and metabolized in the liver where it stimulates fructolysis, glycolysis, lipogenesis, and glucose production. This may result in hypertriglyceridemia and fatty liver. Therefore, understanding the mechanisms underlying intestinal and hepatic fructose metabolism is important. Here we review recent evidence linking excessive fructose consumption to health risk markers and development of components of the Metabolic Syndrome.

Keywords: fructose; hypertriglyceridemia; metabolic syndrome; metabolism.

Figure 1

Metabolism of fructose in the intestine and liver. Fructose is in the small intestine metabolized by ketohexokinase (KHK) into fructose-1-phosphate (F-1-P) [19]. F-1-P is then cleaved by aldolase B into dihydroxyacetone phosphate and glyceraldehyde. Glyceraldehyde is phosphorylated by triokinase generating glyceraldehyde 3-phosphate (GAP). GAP and other triose phosphates are resynthesized into glucose via gluconeogenesis or metabolized into lactate or acetyl-CoA, which are oxidized or used for lipogenesis. In the liver, fructose activates the transcription factors carbohydrate-responsive element-binding protein (ChREBP) and sterol regulatory element-binding transcription factor 1c (SREBP1c) and their coactivator peroxisome proliferator-activated receptor-β (PGC1β) [16]. This results in upregulation of pathways that stimulate fructolysis, glycolysis, lipogenesis, and glucose production. Collectively, this results in increased hepatic glucose production, generation of lipid intermediates that may affect hepatic insulin sensitivity, increased expression of APOC3 and increased secretion of triglyceride-rich very-low density lipoproteins (VLDL). The increased APOC3 expression induces increased plasma apoC-III, an inhibitor of lipoprotein lipase and hepatic clearance of lipoprotein remnants [20]. This results in hypertriglyceridemia and accumulation of atherogenic triglyceride-rich lipoprotein (TRL) remnants.