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Fructose Metabolism

 

 

 

 

 

 

 

 

 

 

 

Diets containing large amounts of sucrose (a disaccharide of glucose and fructose) can utilize the fructose as a major source of energy. It should be pointed out that the difference between the amount of fructose available from sucrose obtained from cane or beet sugars is not significantly less than that from corn syrup. Corn syrup is somewhat improperly identified as high fructose corn syrup (HFCS) giving the impression that it contains a large amount of fructose. However, whereas the fructose content of sucrose is 50% (since it is a pure disaccharide of only glucose and fructose), the content in HFCS is only 55%. The reason HFCS has more than 50% fructose is because the glucose extracted from corn starch is enzymatically treated to convert some of the glucose to fructose. This is done in order to make the sugar sweeter which is why it is particularly popular in the food industry. Therefore, any disorder and/or dysfunction (see below), attributed to the consumption of fructose, can be manifest whether one consumes cane or beet sugar or HFCS.

The pathway to utilization of fructose differs in muscle and liver due to the differential distribution of fructose phosphorylating enzymes. Hexokinases are a family of enzymes that phosphorylate hexose sugars such as glucose. Four mammalian isozymes of hexokinase are known (Types I–IV), with the Type IV isozyme often referred to as glucokinase. Glucokinase is the form of the enzyme found in hepatocytes and pancreatic β-cells. Several of the hexokinases (but not type IV) can phosphorylate various different hexoses including fructose. In addition to hexokinases, fructose can be phosphorylated by fructokinases. Fructokinases are formally referred to as ketohexokinases (KHK). There are two forms of KHK in mammals that result from alternative splicing of the KHK gene. These two isoforms are called KHK-A (fructokinase A) and KHK-C (fructokinase C). Fructokinase C (KHK-C) has a very high affinity for fructose resulting in rapid phosphorylation with concomitant depletion in ATP. Fructokinase A (KHK-A) has very low affinity for fructose thus, exerting minimal effects on overall fructose metabolism and levels of ATP. Expression of fructokinase C (KHK-C) is seen primarily in the liver, pancreas, kidney, and intestines. Expression of fructokinase A (KHK-A) is more ubiquitous and expressed at highest levels in skeletal muscle. Although both fructokinase C (KHK-C) and fructokinase A (KHK-A) can metabolize fructose, fructokinase C (KHK-C) is considered to be the primary enzyme involved in fructose metabolism because its' KM for fructose is very much lower than that of the fructokinase A (KHK-A) isoform. Because of its very high KM for fructose there is some question as to whether or not fructokinase A (KHK-A) actively metabolizes fructose in vivo.

Muscle, which contains two types of hexokinase (type I and type II), can phosphorylate fructose to F6P which is a direct glycolytic intermediate. However, the affinity of hexokinase for fructose is substantially less than that of fructokinase.

The liver expresses predominantly glucokinase (hexokinase type IV) which is specific for glucose as its' substrate. Due to this pattern of expression there is the requirement for KHK in order to deliver fructose into hepatic glycolysis. Hepatic KHK-C phosphorylates fructose on C–1 yielding fructose-1-phosphate (F1P) which is then hydrolyzed by a specific isoform of aldolase.

Humans express three distinct forms of aldolase; aldolase A, aldolase B, and aldolase C. Aldolase A (fructose-1,6-bisphosphate aldolase) is expressed in most tissues. Aldolase A catalyses the hydrolysis of F1,6BP into two 3-carbon products: dihydroxyacetone phosphate (DHAP) and glyceraldehyde 3-phosphate (G3P). The aldolase A reaction proceeds readily in the reverse direction, being utilized for both glycolysis and gluconeogenesis. The aldolase A gene (gene symbol: ALDOA) is located on chromosome 16p11.2 spanning 7.5 kb and is composed of 12 exons that encode a 363 amino acid protein. Aldolase B is expressed primarily in the liver but also to some degree in the kidney and small intestine. Aldolase B is unique from the other two isoforms in that it can catalyze the hydrolysis of both fructose-1,6-bisphosphate and fructose-1-phosphate with equal affinity. The aldolase B enzyme is encoded by the ALDOB gene which is located on chromosome 9q21.3–q22.2 and is composed of 9 exons that produce a protein of 363 amino acids. Aldolase C is expressed in the brain. The aldolase C enzyme is encoded by the ALDOC gene which is located on chromosome 17cen–q12 and is composed of 10 exons that produce a protein of 364 amino acids.

 In the liver, aldolase B can utilize both F-1,6-BP and F1P as substrates. Therefore, when presented with F1P the enzyme generates DHAP and glyceraldehyde. The DHAP is converted, by triose phosphate isomerase (TPI), to G3P and enters glycolysis. The glyceraldehyde can be phosphorylated to G3P by glyceraldehyde kinase or converted to DHAP through the concerted actions of alcohol dehydrogenase, glycerol kinase and glycerol phosphate dehydrogenase.

Reactions of fructose metabolism

Entry of fructose carbon atoms into the glycolytic pathway in hepatocytes, kidney, and small intestine.

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Fructose Effects on Food Intake

As pointed out in the Glycolysis page, glucose is the primary fuel used for energy production in the brain. When glucose is metabolized within the hypothalamus, a signaling pathway is initiated that ultimately results in the suppression of food intake. More detailed information on the role of the hypothalamus in the control of food intake can be found in the Gut-Brain Interrelationships page. The principal participants in this signaling cascade include AMPK, acetyl-CoA carboxylase (ACC), and the product of the ACC reaction, malonyl-CoA. The mechanism by which AMPK and ACC are regulated, ultimately resulting in altered levels of malonyl-CoA are detailed in the Lipid Synthesis page. Briefly, activation of AMPK results in the phosphorylation of ACC resulting in reduced activity of the latter enzyme. Conversely, when AMPK activty falls the phosphorylation state of ACC falls resulting in increased production of malonyl-CoA. When glucose oxidation is increased in the hypothalamus there is a resultant dephosphorylation and inactivation of AMPK and thereby, activation of ACC. The resultant rise in hypothalamic malonyl-CoA is correlated to reduced expression of several orexigenic peptides (e.g. ghrelin, NPY, and AgRP) concomitant with activated expression of several anorexigenic peptides (e.g. α-MSH and CART). These changes in neuropeptide expression result in suppressed food intake while simultaneously increasing overall energy expenditure.

In contrast to the anorexigenic effect of hypothalamic glucose metabolism, the metabolism of fructose in the brain exerts an orexigenic effect. Although the overall mechanisms by which fructose exerts this orexigenic effect are complex, it is due, in part, to the fact that the brain, like the liver, possesses a unique set of sugar transporters and metabolizing enzymes that enables fructose to bypass the PFK-1 catalyzed step of glycolysis. The PFK-1 catalyzed reaction is the rate-limiting step in glycolysis and is critical in the overall regulation of ATP production and consumption. Since hypothalamic fructose metabolism bypasses this important regulatory step its metabolism rapidly depletes ATP in the hypothalamus. When ATP levels fall there is a concomitant rise in AMP which results in activation of AMPK. Activation of AMPK results in phosphorylation and inhibition of ACC which then results in decreased malonyl-CoA levels in the hypothalamus. Therefore, although glucose and fructose utilize the same signaling pathway to control food intake they act in an inverse manner and have reciprocal effects on the level of hypothalamic malonyl-CoA.

Numerous experiments in animals have implicated malonyl-CoA as a key intermediate in the regulation of feeding behavior and overall energy balance initiated via signaling cascades within the hypothalamus. Initial evidence demonstrating this role of malonyl-CoA was the finding that inhibition of fatty acid synthase (FAS) suppressed food intake. FAS is the primary enzyme in the de novo biosynthesis of fatty acids. The fungal antibiotic, cerulenin, and a related analogue C75, bind to the active site of FAS thereby inhibiting its activity. When these compounds are administered to mice there is a resultant decrease in food intake. Given that inhibition of FAS would be expected to result in an accumulation of its substrate, malonyl-CoA, it was suspected that malonyl-CoA may be a participant in the observed effects. Indeed, intra-cerebrovascular (icv) injection of C75 results in increased levels of hypothalamic malonyl-CoA. Importantly, this effect can be reversed by inhibitors of ACC, the enzyme which synthesizes malonyl-CoA from acetyl- CoA. Further research demonstrated that the anorexigenic effects of FAS inhibitors was due to their ability to rapidly suppress hypothalamic expression of NPY and AgRP, two key orexigenic peptides, while increasing the expression of α-MSH and CART, two key anorexigenic peptides.

Malonyl-CoA levels in the hypothalamus correlate well with nutritional state. Fatty acid synthesis in other tissues, such as the liver and adipose tissue, occurs primarily during energy surplus. Malonyl-CoA, regulates energy metabolism in the liver through two opposing mechanisms. It serves as the substrate for FAS during de novo fatty acid synthesis while at the same time inhibiting mitochondrial fatty acid oxidation through its' action as an allosteric inhibitor of carnitine palmitoyltransferase 1 (CPT1). Inhibition of CPT1 by malonyl-CoA prevents entry of fatty acids into the mitochondria, thereby inhibiting oxidation. During periods when energy expenditure exceeds intake, such as during fasting, malonyl-CoA levels in the hypothalamus are low. Following food intake there is a rapid rise in hypothalamic malonyl-CoA levels. The changes in hypothalamic malonyl-CoA levels are followed quickly by changes in expression of orexigenic and anorexigenic peptides. In the fasting state NPY and AgRP levels are high, whereas α-MSH and CART levels are low. Upon re-feeding this pattern immediately inverts.

Genetic manipulation of hypothalamic malonyl-CoA levels has also been informative. For example, disruption of FAS gene expression in the hypothalamus results in increased malonyl-CoA levels and decreases in body weight and fat content. Concomitant with disruption of hypothalamic FAS gene expression is an increase in malonyl-CoA concentration. Additionally, the levels of orexigenic peptides decrease while levels of anorexigenic peptides increase leading to suppression of food intake. Conversely, genetic manipulation of the expression of malonyl-CoA decarboxylase (MCD) has the opposite effects to those seen by disruption of FAS expression. MCD functions in opposition to ACC in that it is responsible for the conversion of malonyl-CoA to acetyl-CoA. In fact ACC and MCD are reciprocally regulated to ensure adequate regulation of fatty acid synthesis and fatty acid oxidation. Overexpression of MCD within the hypothalamus results in increases in both food intake and body weight and also marked increases in body fat content (adiposity). Additionally, when MCD expression is increased within the hypothalamus there is an observed inhibition of the FAS inhibitor (C75)-induced suppression of food intake. These results obtained with forced expression of MCD provide strong evidence that hypothalamic malonyl-CoA acts as an indicator of energy status and participates in the regulation of feeding behavior. In addition, these results indicate that malonyl-CoA, rather than fatty acids, is the effector that regulates energy homeostasis.

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Fructose Utilization and Associated Metabolic Dysfunction

Consumption of fructose has been shown to be highly correlated with the development of diabetes, obesity and the metabolic syndrome. Consumption of soft drinks (high in HFCS) is associated with an increased risk for obesity in adolescents and for type 2 diabetes in young and middle-aged women. Excess fruit juice (also rich in fructose) is associated with the development of obesity in children. One distinction between fructose and glucose metabolism is that the metabolism of fructose results in increases in serum uric acid concentration. The increased production of uric acid as a result of fructose metabolism is related to the activity of fructokinase (KHK). The activity of fructokinase (KHK) is different from the other hexokinases by virtue of the fact that it induces transient ATP depletion in the cell. The mechanism is due to the fact that fructokinase (KHK) rapidly phosphorylates fructose to fructose-1-phosphate resulting in marked ATP depletion. The activity of fructokinase (KHK) is not subject to feed-back inhibition such as is the case for glucose metabolism, thus the ATP depletion is profound. Since the majority of fructose metabolism occurs in the liver, the effects of this ATP depletion are exerted on numerous important hepatic metabolic processes. The depletion in ATP is also associated with intracellular phosphate depletion and dramatic increases in AMP generation. Both of the latter stimulate the activity of the purine nucleotide catabolic enzyme AMP deaminase increasing degradation of AMP ultimately to uric acid.

Elevated serum uric acid is a good predictor for the development of obesity and hypertension. Uric acid is the byproduct of purine nucleotide catabolism. Gout is a disorder that is related to excess production and deposition of uric acid crystals with the root cause of gout being hyperuricemia. Therefore, excess consumption of HFCS can also result in, and exacerbate symptoms of gout.

Consumption of fructose by laboratory animals results in their developing several features of metabolic syndrome, including obesity, visceral fat accumulation, fatty liver, and elevated insulin and leptin levels. It is likely that the increase in leptin following fructose consumption represents leptin resistance, which could account for the increased food intake observed in fructose-fed animals. All of these phenomena associated with fructose consumption, including hyperuricemia, can be blocked in laboratory animals when both fructokinase C (KHK-C) and fructokinase A (KHK-A) isoforms are eliminated. The relationship between fructose metabolism-mediated hyperuricemia and development of the metabolic syndrome can also be demonstrated by the fact that treating animals with allopurinol, a drug used to lower uric acid levels in gout patients, partially prevented the fructose-induced metabolic syndrome.

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Essential Fructosuria

Essential fructosuria is a benign metabolic disorder caused by the lack of fructokinase which is normally present in the liver, pancreatic islets and kidney cortex. The fructosuria of this disease depends on the time and amount of fructose and sucrose intake. Since the disorder is asymptomatic and harmless it may go undiagnosed.

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Hereditary Fructose Intoleracne

Hereditary fructose intolerance (HFI) is a potentially lethal autosomal recessive disorder resulting from a lack of aldolase B (gene symbol: ALDOB) which is normally expressed in the liver, small intestine and kidney cortex. The incidence of HFI is on the order of 1 in 20,000 live births. The disorder is characterized by severe hypoglycemia and vomiting following fructose intake. Prolonged intake of fructose by infants with this defect leads to vomiting, poor feeding, jaundice, hepatomegaly, hemorrhage and eventually hepatic failure and death. Patients will remain symptom free on a diet devoid of fructose and sucrose.

The biochemistry of aldolase B deficiency is complex due to the fact that this enzyme can catalyze three distinct reactions. Under normal conditions, the tissues that express aldolase B utilize this enzyme for the cleavage of F1,6BP within the context of glycolysis. Like aldolase A, aldolase B can also catalyze the condensation of DHAP and glyceraldehyde-3-phosphate to form F1,6BP in the gluconeogenic direction. Since the liver, kidney, and small intestine all contribute to endogenous glucose production (gluconeogenesis), this action of aldolase B is physiologically significant. With consumption of sucrose or fructose, the ability of aldolase B to cleave hepatic fructose-1-phosphate, generated via the fructokinase reaction, to glyceraldehyde and DHAP becomes physiologically relevant.

The primary cause of the manifesting symptoms in HFI is the trapping of phosphate (Pi) in fructose-1-phosphate and the consequent reduction in the pool of ATP via the fructokinase reaction. The trapping of the inorganic phosphate pool and ATP depletion leads to global reduction in all cellular processes that rely on phosphorylation or ATP. The loss of the inorganic phosphate (Pi) pool impairs glycogen breakdown due to the role of Pi as a substrate for phosphoryltic action of hepatic glycogen phosphorylase. This, therefore, contributes to the severe hypoglycemia upon ingestion of fructose or sucrose. The depletion of the phosphate pool also activates AMP deaminase resulting in increased nucleotide catabolism. This latter effect is the cause of the hyperuricemia associated with HFI. As the level of fructose-1-phosphate increases, it inhibits the fructokinase reaction in a feedback mechanism. Inhibition of fructokinase leads to reduced hepatic fructose uptake contributing to the fructosemia of HFI.

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Fructose-1,6-Bisphosphatase Deficiency

Hereditary fructose-1,6-bisphosphatase (F1,6BPase) deficiency is an autosomal recessive disease. The disease results from inherited defects in the hepatic F1,6BPase gene (gene symbol: FBP1). Loss of fully functional FBP1 results in severely impaired hepatic gluconeogenesis and leads to episodes of hypoglycemia, apnea, hyperventilation, ketosis and lactic acidosis. These symptoms can take on a lethal course in neonates. Later in life episodes are triggered by fasting and febrile infections. Because of the existence of two FBP genes (FBP1 and FBP2) it is not possible to utilize assays for F1,6BPase deficiency in the white blood cells of suspected patients.

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Michael W King, PhD | © 1996–2017 themedicalbiochemistrypage.org, LLC | info @ themedicalbiochemistrypage.org

Last modified: July 27, 2016