Molecular aspects of fructose metabolism and metabolic disease

Abstract

Excessive sugar consumption is increasingly considered as a contributor to the emerging epidemics of obesity and the associated cardiometabolic disease. Sugar is added to the diet in the form of sucrose or high-fructose corn syrup, both of which comprise nearly equal amounts of glucose and fructose. The unique aspects of fructose metabolism and properties of fructose-derived metabolites allow for fructose to serve as a physiological signal of normal dietary sugar consumption. However, when fructose is consumed in excess, these unique properties may contribute to the pathogenesis of cardiometabolic disease. Here, we review the biochemistry, genetics, and physiology of fructose metabolism and consider mechanisms by which excessive fructose consumption may contribute to metabolic disease. Lastly, we consider new therapeutic options for the treatment of metabolic disease based upon this knowledge.

Keywords: ALDOB; ChREBP; GLUT5; KHK; NAFLD; TKFC; cardiometabolic disease; fructose; insulin resistance; lipogenesis; steatosis; uric acid.

Figure 1.. Organismal fructose metabolism and first pass extraction in the gut.

Following ingestion of a large oral fructose load, fructose is absorbed into intestinal epithelial enterocytes. A portion of this fructose is phosphorylated by KHK within the enterocyte and is converted to glucose, lactate, glycerate and other organic acids which travel via to the portal vein to the liver. Portal fructose concentrations can transiently reach concentrations as high as ~1 mM. Fructose reaching the liver is efficiently extracted by hepatocytes and phosphorylated by KHK where it can be used for glucose production, lipogenesis, glycogen synthesis and energetic purposes. Peripheral blood fructose concentrations transiently peak at levels ~10-fold lower than peak portal levels.

Figure 2.. Fructolysis and associated biochemistry.

Fructose is transported into enterocytes and hepatocytes via GLUT5 and GLUT2, respectively. Upon entering the cells, fructose is phosphorylated by KHK to F1P. Energy depletion resulting from robust fructose phosphorylation leads to activation of AMPD2 and uric acid production. F1P is cleaved by ALDOB to DHAP and GA. GA is phosphorylated by triose-kinase (TKFC) to GA3P. Both DHAP and GA3P mix with triose-phosphates common to the glycolytic and gluconeogenic carbon pools. In hepatocytes, F1P allosterically inhibits PGYL to enhance glycogen synthesis and disrupts the interaction between GCK and GCKR allowing GCK to translocate from the nucleus to the cytoplasm and catalyze phosphorylation of glucose further increasing the hexose- and triose-phosphate carbon pools. Fructose-derived substrate has numerous fates, including use in de novo lipogenesis (DNL) both through direct and indirect pathways via microbiome derived acetate. KHK, ketohexokinase; AMPD3, adenosine deaminase; IMP, inosine monophosphate; ALDOB, aldolase B; TKFC, triokinase and FMN cyclase; GA, glyceraldehyde; DHAP, dihydroxyacetone phosphate; GA3P, glyceraldehyde 3-phosphate; PYGL, glycogen phosphorylase L; GYS2, glycogen synthase 2; PKLR, pyruvate kinase, liver and red blood cell; PEP, phosphoenolpyruvate.

Figure 3.. Fructose activates metabolic gene expression.

Fructose derived metabolites act as signaling molecules to activate metabolic transcriptional programs. F1P derived from fructose metabolism activates GCK and the combination of fructose- and glucose-derived hexose phosphates activate ChREBP, which coordinately regulates enzymes involved in fructolysis, glycolysis, glucose production, lipogenesis and VLDL packaging and export. Fructose-derived metabolites may also activate SREBP1c. Both ChREBP and SREBP1c are coactivated by PGC1β to further coordinate and enhance transcription of metabolic programs. ACLY, ATP citrate lyase; ACACA, acetyl-CoA carboxylase α; FASN, fatty acid synthase; GPAT, glycerol-3-phosphate acyltransferases; AGPAT, acylglycerol-3-phosphate acyltransferase; DGAT, diacylglycerol acyltransferase; MTTP, microsomal triglyceride transfer protein; TM6sf2, Transmembrane 6 Superfamily, Member 2; TAG, triacylglycerol; VLDL, very-low density lipoprotein.