Introduction

Fructose is an abundant monosaccharide in the human diet that the body needs to metabolize. It is present in honey, fruits, vegetables, and high-fructose corn syrup used to manufacture beverages (soft drinks) and food. Their consumption results in a significant amount of added sugars entering the diet, approximately half of which is fructose. Sucrose (table sugar) converts to fructose and glucose by acid hydrolysis in the stomach and sucrase-isomaltase cleavage in the small intestine.[1]

Transport and metabolism of fructose do not require insulin; only a few tissues, such as the liver, intestine, kidney, adipose tissue, and muscle, can metabolize it (see Image. The Metabolic Pathway of Fructose). Glucose and fructose have similar metabolic fates because most dietary fructose converts into glucose.[2] The mechanism of fructose sensing helps to understand the metabolism and potential pathophysiological consequences of excessive sugar intake.

Fundamentals

The metabolism of dietary fructose to yield energy is known as fructolysis. The process of fructolysis utilizes most of the same enzymes and metabolic intermediates as the glycolysis pathway. However, unlike glucose, which metabolizes directly throughout the body, fructose metabolizes predominantly in the liver. It directs toward the replenishment of liver glycogen and the synthesis of triglycerides.[3][4]

As a result, fructose metabolism produces the same ATP as glucose. However, fructose enters glycolysis without going through the energy investment step; as a result, it yields one extra adenosine triphosphate (ATP). There are 2 pathways to metabolize fructose. The hexokinase in muscle and adipose tissue phosphorylates fructose, which then enters glycolysis.[5] Most of the enzymes found in the liver are glucokinases rather than hexokinases; they do not catalyze the phosphorylation of fructose. In contrast to the hexokinase pathway, fructose is metabolized in the liver by the fructose 1-phosphate pathway.[6]

Issues of Concern

Excess fructose consumption increasingly influences the global epidemics of diabetes mellitus, obesity, and the associated cardiometabolic risks.[7] Moreover, the unique metabolic properties of fructose potentiate profound metabolic consequences like hypercholesterolemia, hypertriglyceridemia, and hyperuricemia.[8]

Cellular Level

The majority of cells are incapable of metabolizing fructose directly. Instead, all the reactions involved in fructose metabolism occur in the cytosol of cells, liver, muscle, adipose tissue, gut, and sperm.[9]

Molecular Level

Absorption

The majority of ingested fructose is absorbed passively via glucose transporter 5 (GLUT5), also known as solute carrier family 2 facilitated glucose transporter member 5 (SLC2A5), which has a high binding affinity for fructose with a Km of 6 mM. Then GLUT 2 or SLC2A2 transports it into the bloodstream. The transport rate of fructose and intestinal GLUT5 mRNA levels is deficient during gestation. It rapidly increases after weaning regardless of diet, but they are further enhanced by introducing fructose-rich diets. In addition, high-fructose food enhances the thioredoxin interacting protein (TXNIP) in the intestine, which binds and regulates GLUT5-mediated fructose transport in the intestine. A carbohydrate-responsive element-binding protein (ChREBP) transcription factor regulates GLUT5 and TXNIP expression, which is necessary for systemic fructose tolerance.[10]

Proper Metabolic Pathway

Adipose tissue and muscle

In adipose tissue and muscle, hexokinase phosphorylates fructose to synthesize fructose 6-phosphate, which then enters into glycolysis. Hexokinase, on the other hand, phosphorylates the majority of hexoses, including glucose. Furthermore, the Km of hexokinase for fructose is exponentially higher than that of glucose. Therefore, as glucose is a more favorable substrate for hexokinase, it competitively inhibits fructose phosphorylation by hexokinase.[11]

Liver, kidney, and intestine

In the liver, kidney, and intestine, fructokinase (or ketohexokinase) phosphorylates fructose at the first carbon position to synthesize fructose 1-phosphate. Thus, most fructose is incorporated into the metabolic pathway through the fructokinase-catalyzed reaction, as glucokinase has poor substrate specificity for fructose. Fructokinase occurs in two different isoforms, isoform A and isoform C. In addition to having a ubiquitous tissue distribution, Isoform A has a lower affinity for fructose, which seems to diminish the amount of fructose available for metabolism by the liver. However, Isoform C is mainly present in the liver, intestine, and kidney and has a high affinity for fructose, leading to the rapid incorporation of fructose for metabolism. Then, fructose 1-phosphate aldolase or aldolase B degrades fructose 1-phosphate into dihydroxyacetone phosphate and glyceraldehyde. Finally, dihydroxyacetone phosphate enters glycolysis via triosephosphate isomerase, while triose kinase phosphorylates glyceraldehyde to form glyceraldehyde 3-phosphate. Thus, these 2 triose phosphates degrade by glycolysis or serve as a substrate for gluconeogenesis, the final fate of a considerable proportion of fructose metabolism in the liver.[12]

Polyol pathway

In the polyol pathway, glucose converts into sorbitol by aldolase reductase. Sorbitol further oxidizes into fructose by sorbitol dehydrogenase, accounting for fructose's appearance in seminal plasma. A seminal vesicle, hepatocytes, and ovarian cells express aldose reductase and sorbitol dehydrogenase, which synthesize fructose from glucose.[13][14]

Regulation [15]

Regulation of fructose metabolism in the liver

The processing of fructose in the liver is not controlled by hormone or allosteric mechanisms, and fructose bypasses the rate-limiting step of glycolysis catalyzed by phosphofructokinase 1 (PFK 1). Hence, fructose metabolism is less tightly regulated and occurs at a much faster rate than glucose. Furthermore, aldolase-B performs a lysis step distinct from aldolase in glycolysis, producing dihydroxyacetone phosphate and glyceraldehyde due to its activity. In contrast to aldolase products, the latter must be phosphorylated to function.

Regulation at fructose uptake and phosphorylation

Fructose 1-phosphate acts as a positive allosteric modulator of glucokinase. The possible allosteric activity and high Km of glucokinase are due to the attachment of inhibitory glucokinase-regulatory protein inside the nucleus, which decreases the affinity of glucokinase for fructose. The translocation of the glucokinase-regulatory protein complex to the nucleus results in the inhibition of glucokinase activity. To relieve this inhibition, fructose-1-phosphate binds to the glucokinase-regulatory protein and stabilizes the dissociated protein. Insulin and postprandial glucose stimulate the dissociation of glucokinase-regulatory protein and transport it from the nucleus. Fructose phosphorylation is predominantly dependent on fructose concentration in tissues such as the liver, and a rise in fructose concentration leads to a decrease in cellular ATP.

Metabolites of fructose enter the triose phosphate pool distal to PFK 1, bypassing the PFK 1 regulatory step. Thus, fructose loads can cause significant, rapid augmentations in the triose and hexose phosphate pools, potentially providing more substrate for all central carbon metabolic pathways, such as glycolysis, gluconeogenesis, glycogenesis, oxidative phosphorylation, and lipogenesis, because hepatic fructolysis is unrestricted.

Comparison of Fructolysis and Glycolysis [16]

Function

Fructose promotes the uptake and storage of glucose in the liver. Fructose also helps to speed up the oxidation of carbohydrate stores after a meal.[17]

Fructose provides the majority of the energy required for the mobility of spermatozoa. Seminal vesicles are responsible for the secretion of fructose. However, some people experience azoospermia due to a blockage in the duct of seminal vesicles. In such individuals, semen is analyzed for fructose concentration. Depending on whether fructose is present, the block will be above the seminal vesicular duct, and if it is absent, the block will be below the seminal vesicles.[18]

Fructose may play a vital role in the maturation of preadipocytes, allowing them to store more fat.[19] Fructose may also benefit individuals in strenuous physical activity by sustaining hepatic gluconeogenesis and providing additional energy to contract skeletal muscle in lactate.[20]

Clinical Significance

Hereditary Fructose Intolerance

hereditary fructose intolerance, or hereditary fructosemia, is an autosomal recessive inborn fructose metabolism error due to the aldolase B deficiency (mutation in ALDOB gene) or fructose 1,6-bisphosphate aldolase in the liver, intestine, and kidney. Affected infants are primarily asymptomatic until they consume fructose or sucrose through their diet (fruits, table sugar, honey) around weaning. After consuming fructose, fructose 1-phosphate builds up in the liver and kidney and causes toxic symptoms. In addition, fructose 1-phosphate inhibits fructokinase and decreases hepatic uptake of fructose, resulting in fructosemia. It is characterized by nausea, vomiting, abdominal pain, jaundice, hepatomegaly, and metabolic abnormalities such as hypoglycemia, hyperuricemia, hypermagnesemia, and hypophosphatemia.

Biochemical basis of hypoglycemia

Fructose converts into fructose 1-phosphate and gets trapped inside the hepatocytes. This leads to depletion of inorganic phosphate, impairment of ATP synthesis and lack of cellular ATP, impairment in gluconeogenesis, and finally, hypoglycemia. In addition, fructose 1-phosphate allosterically inhibits hepatic glycogen phosphorylase, leading to postprandial hypoglycemia and glycogen accumulation in the liver.

Biochemical basis of liver and kidney dysfunction

Liver mitochondria cannot perform oxidative phosphorylation as sequestration of inorganic phosphate in the form of fructose 1-phosphate. The ATP levels plummet, making it impossible for the liver to perform normal work functions. In addition, the ATP-dependent cation pumps fail to maintain normal ion gradients, causing cell damage by osmotic lysis.

Aldolase B is the predominant form of aldolase in proximal renal tubules. The interaction between aldolase B and vacuolar type-ATPase (V-ATPase) is critical for the proximal renal tubules for proper acidification function regarding proton transport across the tubules and endosomal acidification. Thus, the absence of V-ATPase-aldolase B interaction may contribute to renal tubular dysfunction in aldolase B deficiency.

Impairment in protein synthesis, hyperuricemia, and magnesium release may be responsible for liver and kidney dysfunction. In addition, fructose 1-phosphate is a potent competitive inhibitor of phosphomannone isomer, an enzyme involved in the first step of protein N-glycosylation. Thus, defective N-glycosylation leads to improper protein synthesis, folding, and trafficking.

Urine is positive for the reducing sugars test but negative for the glucose dipstick test. An aldolase B enzyme assay in a liver biopsy and DNA profiling by allele-specific probes serve as confirmatory diagnostic tests. In addition, monitoring increased carbohydrate-deficient transferrin by transferrin isoelectric focusing and increased activity of aspartylglucosaminidase should be used for disease follow-up to assess compliance with dietary restrictions.

An early diagnosis of fructose intolerance and the prompt implementation of dietary measures to combat fructose intolerance is critical. Therefore, the primary strategy of therapy is to eliminate dietary fructose, sucrose, and sorbitol. Using fructose-containing intravenous fluids, medications, or infant formulas is not recommended during hospitalization. A sugar-free, water-soluble multivitamin is prescribed daily to prevent micronutrient deficiencies.[21][22]

Essential Fructosuria 

Essential fructosuria, or benign fructosuria, is an autosomal recessive disorder due to a deficiency of fructokinase that converts fructose into fructose 1-phosphate. Hepatocytes cannot trap fructose in the form of fructose 1-phosphate, which leads to the accumulation of fructose in the blood, and excess fructose readily excretes in the urine because fructose has a low renal threshold. It is not called fructosemia because hexokinase in extra-hepatic tissue metabolizes increased fructose levels in the blood. As a result, the level of fructose in the blood is not consistently elevated. It is an entirely benign condition without any symptoms or complications. It is diagnosed accidentally during urine examination, positive for reducing sugar and negative for glucose dipstick test. Urine chromatography for fructose serves as a confirmatory test to diagnose benign fructosuria. There is no need for any treatment or dietary restriction.[23]

Increased fructose levels are associated with myocardial infarction and aging. Fructose glycates at a rate tenfold that of glucose, and reduced antioxidant activity contributes to myocardial infarction.[24][25]