Ketohexokinase-Dependent Metabolism of Fructose Induces Proinflammatory Mediators in Proximal Tubular Cells

Abstract

Increased consumption of fructose may play an important role in the epidemic of metabolic syndrome and may presage the development of diabetes, cardiovascular disease, and chronic kidney disease. Once in the cell, fructose is phosphorylated by ketohexokinase (KHK), leading to consumption of ATP, formation of AMP, and generation of uric acid through xanthine oxidoreductase (XOR). This study aimed to examine the direct effects of fructose in human kidney proximal tubular cells (HK-2) and whether they are mediated by the fructose metabolism via KHK. At a similar concentration to that observed in peripheral blood after a meal, fructose induced production of monocyte chemotactic protein 1 (MCP-1) and reactive oxygen species in HK-2 cells. Knockdown of KHK by stable transfection with small hairpin RNA demonstrated that these processes were KHK dependent. Several antioxidants, including specific inhibitors of NADPH oxidase and XOR, prevented MCP-1 secretion. We detected XOR mRNA in HK-2 cells and confirmed its activity by identifying uric acid by mass spectrometry. Fructose increased intracellular uric acid, and uric acid induced production of MCP-1 as well. In summary, postprandial concentrations of fructose stimulate redox-and urate-dependent inflammatory mediators in proximal tubular cells.

Intestinal proteome changes during infant necrotizing enterocolitis

“…The progressing inflammatory lesions changed various metabolic pathways, including lowered metabolism of fructose (ketohexokinase isoform b) (27) and alcohol (aldehyde dehydrogenase) in the small intestine. The higher level of pyruvate kinase in NEC-affected small intestine and lower level of pyruvate dehydrogenase in NEC-affected colon indicate effects on pyruvate metabolism in NEC tissues.…”

Fructose: Pure, White, and Deadly? Fructose, by Any other Name, is a Health Hazard

“…29,30 Failure to suppress caloric intake to offset the calories from calorie-sweetened beverages is part of the mechanism for increased energy intake and the risk for obesity. [26][27][28] Drinking sugar-sweetened beverages at lunch did not suppress intake of solid food; rather, the calories from beverages added on to total calorie intake.…”

“…Upon entering the liver, glucose is phosphorylated at the 6-position to form glucose-6-phosphate, whereas fructose is phosphorylated at the 1-position by ketohexokinase to form fructose-1-phosphate. 30 The fructose-1-phosphate is readily converted to the backbone of triglyceride, whereas glucose-6-phosphate is not so readily converted to triglyceride because its metabolism is regulated by phosphofructokinase. This probably explains why fructose-but not glucosestimulates the formation of lipids in the liver and increases circulating levels of triglycerides, particularly at night.…”

The Not-so-Sweet Side of Fructose

“…16 Does fructose itself have direct adverse effects on the renal tubular cells to cause kidney injury? In this issue of JASN, Cirillo et al 17 investigate the potential direct effects of fructose on human proximal tubular epithelial cells. The same group previously reported that high-fructose diets accelerate the progression of CKD in the rodent remnant kidney model associated with an inflammatory response in the kidney featuring tubulointerstitial inflammation with monocyte-macrophage infiltration and increased expression of monocyte chemotactic protein 1 (MCP-1) in the renal cortex.…”