"Sweet death": Fructose as a metabolic toxin that targets the gut-liver axis

Abstract

Glucose and fructose are closely related simple sugars, but fructose has been associated more closely with metabolic disease. Until the 1960s, the major dietary source of fructose was fruit, but subsequently, high-fructose corn syrup (HFCS) became a dominant component of the Western diet. The exponential increase in HFCS consumption correlates with the increased incidence of obesity and type 2 diabetes mellitus, but the mechanistic link between these metabolic diseases and fructose remains tenuous. Although dietary fructose was thought to be metabolized exclusively in the liver, evidence has emerged that it is also metabolized in the small intestine and leads to intestinal epithelial barrier deterioration. Along with the clinical manifestations of hereditary fructose intolerance, these findings suggest that, along with the direct effect of fructose on liver metabolism, the gut-liver axis plays a key role in fructose metabolism and pathology. Here, we summarize recent studies on fructose biology and pathology and discuss new opportunities for prevention and treatment of diseases associated with high-fructose consumption.

Keywords: NASH; cancer; fructos; gut inflammation; metabolic disease.

Figure 1.. Fructose metabolism

After ingestion, fructose is metabolized either in the gastrointestinal tract or the liver. Fructose is initially mobilized by the constitutively active enzyme ketohexokinase (KHK), which converts it to fructose 1 phosphate (F1P) that is subsequently cleaved by the rate limiting enzyme aldolase B to glyceraldehyde (GA) and dihydroxyacetone phosphate (DHAP). GA undergoes a series of subsequent metabolic conversions to form pyruvate, from which it can be converted to lactate, undergoes oxidative metabolism via the tricarboxylic acid (TCA) cycle, or feed de novo lipogenesis after the generation of acetyl and malonyl coenzyme A (CoA), finally generating triacylglyceride (TAG). The formation of malonyl CoA can alter the balance between fatty acid oxidation (FAO) and synthesis through an effect on acetyl-CoA carboxylase (ACC), resulting in the inhibition of AMP-activated protein kinase (AMPK), which stimulates FAO and carnitine palmitoyltransferase I (CPT1), which control the entry of fatty acids into the mitochondrion. ATP citrate lyase (ACLY), which uses cytosolic citrate to generate acetyl-CoA, is also upregulated by fructose consumption. Glyceraldehyde 3-phosphate dehydrogenase (GAPDH) converts DHAP to glycerol-3 phosphate (G3P), which, together with fatty acids, generates TAG.

Figure 2.. Fructose absorption at different sites

Fructose and glucose are absorbed at the apical pole of the enterocyte by glucose transporter (GLUT) 5 and sodium-glucose co-transporter 1 (SGLT-1), respectively. The entry of fructose from the basolateral pole of the enterocyte is facilitated by GLUT5 and possibly GLUT2. Fructose uptake by the liver is primarily due to the action of GLUT2, but GLUT8 may also play a role in this process.

Figure 3.. Schematic summary of proposed mechanisms for fructose-induced hepatosteatosis via the gut-liver axis

Excess fructose consumption can lead to altered microbiota and the production of short chain fatty acids that ultimately stimulate hepatosteatosis. Fructose can also disrupt gut barrier integrity, resulting in systemic endotoxemia, leading to the activation of an inflammatory cascade via macrophage toll-like receptor 4 (TLR4) signaling, thus resulting in tumor necrosis factor (TNF)-induced hepatosteatosis.