Fructose metabolism and metabolic disease (original) (raw)
Fructose concentrations in peripheral plasma are typically about 0.04 mM, can acutely increase 10-fold after fructose consumption, and return to fasting levels within 2 hours (39–41). This rapid clearance is mediated in large part by efficient extraction by the liver. Whereas the liver extracts only 15% to 30% of an oral glucose load, it is capable of extracting 70% of an oral fructose load (42, 43). Following fructose ingestion, plasma fructose can achieve low millimolar concentrations in the portal vein accompanied by peripheral circulation levels of approximately 0.2 mM, indicating that peripheral fructose concentrations rarely exceed the high micromolar range (44).
The SLC2A2 glucose transporter, also known as GLUT2, has lower affinity for fructose (_K_m = 11 mM) than GLUT5 (45). GLUT2 is a minor contributor to intestinal fructose transport (45), whereas it is likely a major contributor to hepatic fructose uptake, since GLUT5 is not robustly expressed in the liver (46, 47). SLC2A8, also known as GLUT8, may also contribute to hepatocellular fructose transport (48). Fructose is a poor substrate for the hepatic hexokinase glucokinase (GCK). Instead, ketohexokinase (KHK, also known as fructokinase) rapidly phosphorylates fructose to generate fructose-1-phosphate (F1P). KHK’s high activity and insensitivity to cellular energy status account for the liver’s ability to efficiently extract fructose. F1P is metabolized to dihydroxyacetone phosphate (DHAP) and glyceraldehyde 3-phosphate (G3P), which enter the glycolytic/gluconeogenic metabolite pools (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.
Cellular metabolic status and energy status tightly regulate the phosphofructokinase (PFK) step in glycolysis, which limits hepatic glycolytic flux (49). In contrast, fructose-derived metabolites enter the triose-phosphate pool distal to PFK and therefore bypass this restriction. As hepatic fructolysis is unrestricted, fructose loads can lead to large, rapid expansions in the hexose- and triose-phosphate pools, potentially providing increased substrate for all central carbon metabolic pathways, including glycolysis, glycogenesis, gluconeogenesis, lipogenesis, and oxidative phosphorylation.
The disposition of fructose-derived carbon among the major metabolic pathways depends on the overall nutritional and endocrine status of the animal as well as the status of key regulatory checkpoints in intermediary metabolism. For instance, in starved animals, low levels of fructose-2,6-biphosphate inhibit PFK activity and glycolysis and activate fructose-1,6-biphosphatase and glucose production (50). Thus, in a starved animal, fructose-derived triose-phosphates are preferentially routed through the gluconeogenic path (51, 52). The fate of ingested fructose may also depend on coingested nutrients. For instance, infusing physiological concentrations of fructose to fed rats and humans increases serum glucose and lactate levels without affecting hepatic glycogen accumulation (53, 54). However, when fructose is infused with glucose, which stimulates insulin secretion, marked glycogen accumulation occurs (55). Chronic fructose consumption can affect metabolic gene expression programs that further affect fructose disposition. These mechanisms will be described in greater detail below.
Although the liver metabolizes the majority of ingested fructose, the intestine itself can metabolize up to 30% of an oral fructose load (56, 57). All of the fructolytic enzymes are highly expressed in the small intestine and notably in the jejunum, where the highest levels of GLUT5 are observed (58). Similarly to GLUT5, intestinal expression of fructolytic and gluconeogenic enzymes including glucose-6-phosphatase (G6PC) increases upon fructose feeding (59) and depends on GLUT5 and KHK activity (60). However, most prandial fructose is not metabolized in the intestine but rather passes via the portal vein to the liver (61, 62).
In addition to providing substrate for metabolic processes, hepatic fructose metabolism generates specific metabolites that also perform signaling functions (Figure 2). Importantly, F1P, the fructose-specific metabolite produced by KHK, exerts strong positive regulatory control on GCK by promoting its release from the inhibitory GCK regulatory protein (GCKR). GCKR sequesters GCK in an inactive state in the nucleus (63–65). “Catalytic” amounts of fructose, in part through activation of GCK, can promote hepatic glucose uptake and phosphorylation, leading to rapid glycogen accumulation (66). F1P may also enhance glycogen synthesis by allosterically inhibiting glycogen phosphorylase (67, 68). Lastly, F1P also allosterically activates pyruvate kinase, the terminal step in glycolysis, contributing to increased circulating lactate levels following fructose ingestion (69). In rodent liver, hepatic F1P levels increase 10-fold to approximately 1 mM within 10 minutes after fructose ingestion and remain elevated for several hours (70). F1P concentrations of only approximately 200 μM are sufficient to alleviate the inhibitory effect of GCKR on GCK (71). Thus, fructose ingestion is likely to have rapid, robust, and sustained effects on hepatic glucose uptake and intermediary metabolism.
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.
While the efficiency and rapidity with which the liver can extract and phosphorylate ingested fructose are likely important for its role in integrating nutritional and systemic fuel metabolism, this robust metabolism may also have deleterious consequences. For instance, decreases in intracellular free phosphate due to rapid hepatic fructose phosphorylation can increase uric acid production through activation of AMP deaminase, which leads to catabolism of AMP to uric acid (72, 73). Fructose feeding may also stimulate purine synthesis, contributing to uric acid production (74). Increased circulating uric acid levels increase the risk of gout, a condition characterized by painful inflammation due to deposition of uric acid crystals in joints. Indeed, a growing body of evidence implicates sugar intake as a risk factor for gout (75). Moreover, elevated serum uric acid levels and gout are associated with other cardiometabolic risk factors in diverse populations (76–78). A substantial body of work suggests that increased uric acid levels may independently regulate important aspects of metabolism and contribute to cardiometabolic risk (79–83). However, Mendelian randomization studies do not strongly support a causal role for circulating uric acid in mediating cardiometabolic disease (84). The association between uric acid levels and cardiometabolic risk may be indirect and may reflect activation of distinct fructose-regulated processes that contribute both to uric acid production and cardiometabolic risk.
The liver is at a metabolic crossroads and is crucial for gauging nutrient consumption and integrating peripheral nutrient status to regulate systemic fuel storage versus provisioning. While hormones like insulin and glucagon help inform the liver of systemic fuel status, the liver is also well configured to integrate signals derived directly from fuel substrates. In this sense, the signaling properties of fructose-derived F1P, and particularly its regulation of GCK activity, may function as an evolved mechanism allowing the liver to use fructose metabolism to “sense” sugar (i.e., sucrose or high-fructose corn syrup) consumption. Robust physiological activation of hepatic GCK occurs only when fructose-containing sugars are consumed. This activation enhances net hepatic glucose uptake and storage as glycogen and lipid. Interestingly, at supraphysiological/pathological levels, glucose itself can dissociate GCK from GCKR and may contribute to the increased hepatic GCK activity described in obese diabetics and in genetic models of obesity and diabetes (85, 86). Thus, in the setting of uncontrolled diabetes, the liver may aberrantly sense hyperglycemia as a state of increased sugar consumption. Understanding the metabolic effects of hepatic “sugar sensing” may be of consequence for understanding the pathophysiology of diabetes and hyperglycemia.