CHAPTER OUTLINE
Entry of Fructose into Glycolysis
Fructose Consumption and Feeding Behaviors
Metabolic Disruption With Fructose Consumption
High-Yield Terms
High-fructose corn syrup (HFCS): refers to the sugar syrup generated from corn starch by enzymatic conversion of a portion of the glucose to fructose. Commonly contains 55% fructose and identified as HFCS-55
HFCS and sucrose: represent the 2 primary sources of fructose in the human diet
GLUT5 and GLUT2: intestinal sugar transporters responsible for fructose uptake and then delivery to the blood, respectively
Ketohexokinase: two isoforms KHK-A and KHK-C catalyze phosphorylation of fructose to fructose 1-phosphate, also called frucktokinase
Aldolase B: enzyme catalyzing hydrolysis of fructose 1-phosphate to glyceraldehyde and dihydroxyacetone phosphate (DHAP)
Fructose-induced feeding: metabolism of fructose within the brain results in suppression of anorexigenic signals while activating orexigenic signals
Hereditary fructose intolerance: potentially fatal infant disorder resulting from defect in the level of aldolase B activity
Dietary Fructose
Diets containing large amounts of sucrose (a disaccharide of glucose and fructose) can utilize the fructose as a major source of energy. 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% (referred to as HFCS-55). The reason HFCS has more than 50% fructose is because the glucose extracted from corn starch is treated with glucose isomerase to convert most of the glucose to fructose yielding HFCS-90. The HFCS-90 is then mixed with glucose syrup to produce either HFCS-55 or HFCS-42, both of which are used in food preparations. Therefore, any disorder and/or dysfunction, attributed to the consumption of fructose, can be manifest whether one consumes cane or beet sugar or HFCS.
Following ingestion of sucrose or HFCS, it is degraded in the gut through the action of sucrose-isomaltase into its constituent monosaccharides, glucose, and fructose. As indicated in Chapter 7, glucose is absorbed from the lumen of the intestine via the action of SGLT1 and fructose is absorbed via GLUT5. Once in the intestinal enterocyte, the glucose and fructose can enter the blood via GLUT2-mediated transport. Fructose in the blood does not stimulate insulin secretion from the pancreas and its cellular uptake is insulin-independent.
Activation of Fructose
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 and fructose. 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. In addition to hexokinases, fructose can be phosphorylated by fructokinases.
Although both KHK-C and KHK-A can metabolize fructose, KHK-C is considered to be the primary enzyme involved in fructose metabolism because its Km for fructose is much lower than that of the KHK-A isoform.
Muscle, which contains 2 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.
Entry of Fructose into Glycolysis
The liver contains mostly glucokinase (hexokinase type IV), which exhibits substrate specificity for glucose, and, thus, there is the requirement for KHK to utilize fructose in hepatic glycolysis. Hepatic KHK-C phosphorylates fructose on C-1 yielding fructose 1-phosphate (F1P). In liver (as well as in kidney and intestine), the form of aldolase that predominates (aldolase B, also called fructose-1,6-bisphosphate 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 to G3P and enters glycolysis. The glyceraldehyde can be phosphorylated to G3P by triose kinase or converted to DHAP through the concerted actions of alcohol dehydrogenase, glycerol kinase, and glycerol phosphate dehydrogenase.
Fructose Consumption and Feeding Behaviors
As pointed out in the Chapter 10, 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. Details on the role of the hypothalamus in the control of feeding behaviors are found in Chapter 44. The principal participants hypothalamic signaling cascade induced via glucose metabolism includes the enzymes AMPK and acetyl-CoA carboxylase (ACC) and the product of the ACC reaction, malonyl-CoA. Activation of AMPK results in the phosphorylation of ACC resulting in reduced activity of the latter enzyme. Conversely, when AMPK activity declines the phosphorylation state of ACC falls resulting in increased production of malonyl-CoA. When glucose oxidation is increased in the hypothalamus, AMPK undergoes dephosphorylation resulting in reduced activity of the enzyme which, in turn, leads to activation of ACC. The resultant rise in hypothalamic malonyl-CoA is correlated to reduced expression of the primary orexigenic peptides, NPY and AgRP, with a concomitant increase in the expression of the anorexigenic peptides, α-MSH and CART. These changes in neuropeptide expression result in suppressed food intake while simultaneously increasing overall energy expenditure.
High-Yield Concept
Fructokinases are formally referred to as ketohexokinases (KHK). There are 2 forms of KHK in mammals that result from alternative splicing of the KHK gene. These 2 isoforms are called KHK-A and KHK-C. Expression of KHK-C is seen primarily in the liver, pancreas, kidney, and intestines. Expression of KHK-A is more ubiquitous and expressed at highest levels in skeletal muscle.
Because hepatic fructose metabolism directly produces triose phosphates, its metabolism bypasses the hormonal regulation that is exerted on glucose metabolism at PFK1 (6-phosphofructo-1 kinase), and, in addition, there is no allosteric regulation of the process such as occurs at the PFK1 and hexokinase reactions (Figure 11-1).
FIGURE 11-1: Metabolism of fructose. Aldolase A is found in all tissues, whereas aldolase B is the predominant form in liver. (*Not found in liver.) Murray RK, Bender DA, Botham KM, Kennelly PJ, Rodwell VW, Weil PA. Harper’s Illustrated Biochemistry. 29th ed. New York, NY: McGraw-Hill; 2012.
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 enable fructose to bypass the highly regulated PFK1-catalyzed step of glycolysis. Since hypothalamic fructose metabolism bypasses this important regulatory step its metabolism rapidly depletes ATP levels in the hypothalamus resulting in increased AMP levels. The rise in AMP results in activation of AMPK which, in turn, leads to phosphorylation and inhibition of ACC with the result being 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.
Hypothalamic malonyl-CoA is a key intermediate in the regulation of feeding behavior and overall energy balance initiated via signaling cascades within the hypothalamus. If fatty acid synthase (FAS) is inhibited, malonyl-CoA levels rise and is associated with suppression of food intake. Conversely, if ACC activity is inhibited, suppression of feeding behavior with FAS inhibition is reversed. Overall malonyl-CoA levels in the hypothalamus correlate well with nutritional state. 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 refeeding this pattern immediately inverts.
Metabolic Disruption With Fructose Consumption
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 KHK. The activity of 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 KHK rapidly phosphorylates fructose to fructose 1-phosphate resulting in marked ATP depletion. The activity of KHK is not subject to feedback 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 by-product of purine nucleotide catabolism. Gout (see Chapter 32) 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 KHK-C and 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 prevents the fructose-induced metabolic syndrome.
Disorders of Fructose Metabolism
There are 3 primary inherited disorders in fructose metabolism: (1) essential fructosuria, (2) hereditary fructose-1,6-bisphosphatase deficiency, and (3) hereditary fructose intolerance.
Essential fructosuria is a relatively benign autosomal-recessive disorder resulting from defects in hepatic fructokinase (KHK-C). Hyperfructosemia and fructosuria are the principal signs associated with this metabolic defect.
Hereditary fructose-1,6-bisphosphatase deficiency is an autosomal-recessive disorder characterized by episodes of hypoglycemia, ketosis, lactic acidosis, and hyperventilation. The disorder can take a precipitous and often lethal course in the newborn infant. Later episodes are often triggered by fasting and febrile infections. Due to the enzyme defect, gluconeogenesis is severely impaired. Gluconeogenic precursors such as amino acids, lactate, and ketones accumulate as soon as liver glycogen stores are depleted. Patients past early childhood seem to develop normally.
Hereditary fructose intolerance (HFI) is the more severe form of inherited disorders in fructose metabolism which results from defects in the aldolase B gene. Details of this disease are contained in Clinical Box 11-1.
