Fructose metabolism and metabolic disease

Abstract

Increased sugar consumption is increasingly considered to be a contributor to the worldwide epidemics of obesity and diabetes and their associated cardiometabolic risks. As a result of its unique metabolic properties, the fructose component of sugar may be particularly harmful. Diets high in fructose can rapidly produce all of the key features of the metabolic syndrome. Here we review the biology of fructose metabolism as well as potential mechanisms by which excessive fructose consumption may contribute to cardiometabolic disease.

Figure 1. Fructose biochemistry.

Upon entering hepatocytes, fructose is phosphorylated by KHK to F1P. F1P is cleaved to DHAP and glyceraldehyde by ALDOB. Glyceraldehyde is phosphorylated by triose-kinase (TKFC, also known as dihydroxyacetone kinase 2 or DAK) to form the glycolytic intermediate glyceraldehyde 3-phosphate (GA3P). Both fructose-derived DHAP and GA3P enter the glycolytic/gluconeogenic metabolite pool at the triose-phosphate level, and these metabolites have numerous metabolic fates. F1P also allosterically regulates metabolic enzymes (red and green lines) to regulate the disposition of fructose-derived substrate and other metabolic products like uric acid. AMPD3, adenosine deaminase; GA, glyceraldehyde; IMP, inosine monophosphate; MTTP, microsomal triglyceride transfer protein; PYGL, glycogen phosphorylase L; GYS2, glycogen synthase 2; PKLR, pyruvate kinase, liver and red blood cell; PEP, phosphoenolpyruvate; TAG, triacylglycerol.

Figure 2. Fructose-induced gene expression programs.

Fructose metabolism activates transcription factors including ChREBP and SREBP1c and their coactivator PGC1β to coordinately regulate gene expression of metabolic enzymes that contribute to fructolysis, glycolysis, lipogenesis, and glucose production. These metabolic pathways contribute to steatosis, VLDL packaging and secretion, as well as glucose production and the generation of lipid intermediates that may affect hepatic insulin sensitivity and other biological processes. ACACA, acetyl-CoA carboxylase α; FASN, fatty acid synthase; GPAT, glycerol-3-phosphate acyltransferases; AGPAT, acylglycerol-3-phosphate acyltransferase; DGAT, diacylglycerol acyltransferase; DAG, diacylglycerol.

Figure 3. Consequences of fructose overconsumption.

Fructose metabolism in key metabolic tissues including the small intestine, liver, and kidney may contribute to diverse cardiometabolic risk factors including steatosis, increased glucose production, hypertriglyceridemia, increased adiposity, and hypertension. Fructose provides substrate for metabolic processes that contribute to cardiometabolic risk and engages cellular and hormonal signaling systems that regulate these metabolic and pathological processes. LPL, lipoprotein lipase.