Tissue-Specific Fructose Metabolism in Obesity and Diabetes

Abstract

Purpose of review: The objective of this review is to provide up-to-date and comprehensive discussion of tissue-specific fructose metabolism in the context of diabetes, dyslipidemia, and nonalcoholic fatty liver disease (NAFLD).

Recent findings: Increased intake of dietary fructose is a risk factor for a myriad of metabolic complications. Tissue-specific fructose metabolism has not been well delineated in terms of its contribution to detrimental health effects associated with fructose intake. Since inhibitors targeting fructose metabolism are being developed for the management of NAFLD and diabetes, it is essential to recognize how inability of one tissue to metabolize fructose may affect metabolism in the other tissues. The primary sites of fructose metabolism are the liver, intestine, and kidney. Skeletal muscle and adipose tissue can also metabolize a large portion of fructose load, especially in the setting of ketohexokinase deficiency, the rate-limiting enzyme of fructose metabolism. Fructose can also be sensed by the pancreas and the brain, where it can influence essential functions involved in energy homeostasis. Lastly, fructose is metabolized by the testes, red blood cells, and lens of the eye where it may contribute to infertility, advanced glycation end products, and cataracts, respectively. An increase in sugar intake, particularly fructose, has been associated with the development of obesity and its complications. Inhibition of fructose utilization in tissues primary responsible for its metabolism alters consumption in other tissues, which have not been traditionally regarded as important depots of fructose metabolism.

Keywords: Diabetes; Dyslipidemia; Fructose; Insulin resistance; NAFLD; Sugar.

Fig. 1

Pathways of fructose and glucose metabolism. Fructose translocation across the cellular membrane is primarily mediated by glucose transporters (GLUT2, GLUT5), as well as sodium and glucose cotransporters, such as SGLT5. Intracellular fructose metabolism is catalyzed by ketohexokinase (KHK), which converts fructose to fructose 1-phosphate. This reaction is considered to be the rate-limiting step in fructose catabolism. The aldolase (aldo) family of enzymes uses fructose 1-phosphate to produce glyceraldehyde (GA) and DHAP, a common intermediate with glycolysis, which is primarily converted into pyruvate. Pyruvate can then be metabolized to lactate or acetyl-CoA, which is a substrate for fatty acid and sterol synthesis or for incorporation into the TCA cycle. The GA produced from fructose 1-phosphate is more specifically associated with fructose as compared to glucose catabolism and has three fates: (1) it is converted to glycerol via alcohol dehydrogenase (ADH) to serve as a backbone for triglyceride synthesis; (2) it produces glycerate via aldehyde dehydrogenase (ALDH), which can contribute to the production of pyruvate via glycerate kinase (GLYCTK); or (3) it produces GA3P via triose kinase (TKFC). Induction of TKFC is another specific step of fructose metabolism. By converging onto common intermediates, fructose can be converted to glucose and thus support glycogen synthesis. On the other hand, glucose can be endogenously converted to fructose via the polyol pathway. First, glucose is reduced by aldose reductase (AR) to sorbitol, which is subsequently oxidized by sorbitol dehydrogenase (SDH) to fructose. Although the metabolism of glucose and that of fructose converge onto common metabolites, the flux through the glycolytic and fructolytic pathways is starkly different. Glycolysis is highly regulated at the level of phosphofructokinase (PFK) by insulin, ATP, and citrate. Conversely, fructose metabolism is 10 times faster than that of glucose and is not regulated by its end products or by insulin.