Fructolysis
Encyclopedia
Fructolysis refers to the metabolism of fructose
from dietary sources. The metabolism of glucose
through glycolysis
uses many of the same enzyme
s and intermediate structures as those in fructolysis, the two sugars have very different metabolic fates in human metabolism. Unlike glucose, which is metabolized widely in the body, fructose is metabolized almost completely in the liver in humans, where it is directed toward replenishment of liver glycogen
and triglyceride
synthesis.
Fructose is a dietary monosaccharide
present naturally in fruit
s and vegetable
s, either as free fructose or as part of the disaccharide
sucrose
, and as free monosaccharides in honey
. It is also present in the form of refined sugars including granulated sugars (white crystalline table sugar, brown sugar
, confectioner's sugar, and turbinado sugar), refined crystalline fructose
and as high fructose corn syrup
s. Fructose represents about 20% of dietary carbohydrate
intake (60 – 80 g) in most individuals. The typical American diet contains approximately 50% of the carbohydrate as polysaccharide
s or starch
and approximately 50% as mono and disaccharides (sugars, both naturally occurring and refined).
Certain foods, such as apple
s and pear
s, contain considerable amounts of free fructose relative to glucose. They are problematic in this regard, since the fructose (in excess of glucose) is not well absorbed and has been shown to cause osmotic
diarrhea
. The major consumers of apple juice are infants and children, and there are several published reports in the pediatric literature raising concern about the osmotic diarrhea and potential for dehydration
, especially in infants.
Unlike glucose, fructose is not an insulin
secretagogue
. Fructose is also not metabolized in insulin-sensitive peripheral tissues. Fructose is selectively taken up and almost completely metabolized by liver hepatocyte
s (the only other cells capable of metabolizing fructose, under normal conditions, are spermatozoa). Very little fructose escapes the liver, and fructose is not metabolized to any great extent in the small intestine, which lacks the fructose phosphorylating
enzyme fructokinase
.
share many of the same intermediate structures, they have very different metabolic fates in human metabolism. Fructose is metabolized almost completely in the liver in humans, and is directed toward replenishment of liver glycogen
and triglyceride
synthesis, while much of dietary glucose passes through the liver where it is metabolized in skeletal muscle to CO2, H2O and ATP
, and to fat cells where it is metabolized primarily to glycerol phosphate for triglyceride synthesis as well as energy production. The products of fructose metabolism are liver glycogen and de novo lipogenesis of fatty acids and eventual synthesis of endogenous triglyceride can be divided into two main phases: The first phase is the synthesis of the trioses, dihydroxyacetone
(DHAP) and glyceraldehyde
; the second phase is the subsequent metabolism of these trioses either in the gluconeogenic
pathway for glycogen replenishment and/or the complete metabolism in the fructolytic pathway to pyruvate
, which enters the Krebs cycle, is converted to citrate
and subsequently directed toward de novo synthesis of the free fatty acid palmitate
.
(Km
= 0.5 mM, ≈ 9 mg/100 ml), thus trapping fructose for metabolism in the liver.Hexokinase IV
(Glucokinase
), also occurs in the liver and would be capable of phosphorylating fructose to fructose 6-phosphate
(an intermediate in the gluconeoenic
pathway); however, it has a relatively high Km (12 mM) for fructose and, therefore, essentially all of the fructose is converted to fructose-1-phosphate in the human liver. Much of the glucose, on the other hand, is not phosphorylated (Km of hepatic glucokinase (hexokinase IV) = 10 mM), passes through the liver directed toward peripheral tissues, and is taken up by the insulin-dependent glucose transporter, GLUT 4, present on adipose tissue
and skeletal muscle.
Fructose-1-phosphate then undergoes hydrolysis by fructose-1-phosphate aldolase (aldolase B)
to form dihydroxyacetone phosphate (DHAP) and glyceraldehyde; DHAP can either be isomerized to glyceraldehyde 3-phosphate by triosephosphate isomerase or undergo reduction to glycerol 3-phosphate by glycerol 3-phosphate dehydrogenase. The glyceraldehyde produced may also be converted to glyceraldehyde 3-phosphate by glyceraldehyde kinase or converted to glycerol 3-phosphate by glyceraldehyde 3-phosphate dehydrogenase. The metabolism of fructose at this point yields intermediates in gluconeogenic pathway leading to glycogen synthesis, or can be oxidized to pyruvate and reduced to lactate, or be decarboxylated to acetyl CoA in the mitochondria and directed toward the synthesis of free fatty acid, resulting finally in TG synthesis.
and emerges as citrate
directed toward free fatty acid synthesis in the cytosol
of hepatocytes. The DHAP formed during fructolysis can also be converted to glycerol and then glycerol 3-phosphate for TG synthesis. Thus, fructose can provide trioses for both the glycerol 3-phosphate backbone, as well as the free fatty acids in TG synthesis. Indeed, fructose may provide the bulk of the carbohydrate directed toward de novo TG synthesis in humans.
, NADP+-dependent malate dehydrogenase
, citrate lyase
, acetyl CoA carboxylase
, fatty acid synthase
, as well as pyruvate dehydrogenase
. Although not a consistent finding among metabolic feeding studies, high fructose diets have been shown to lead to hypertriglyceridemia
in a wide range of populations including individuals with normal glucose metabolism as well as individuals with impaired glucose tolerance, diabetes, hypertriglyceridemia, and hypertension. The hypertriglyceridemic effects observed are a hallmark of increased dietary carbohydrate, and fructose and appears to be dependent on a number of factors including the amount of dietary fructose consumed and degree insulin resistance
.
‡ = Mean ± SEM activity in nmol/min per mg protein
§ = 12 rats/group
Shafrir, E. Fructose/Sucrose metabolism, its physiological and pathological implications. In Kretchmer, N. & Hollenbeck, CB. Sugars and Sweeteners, CRC Press, Boca Raton:FL, 1991.
and hereditary fructose intolerance. In addition, reduced phosphorylation potential within hepatocytes can occur with intravenous infusion of fructose.
is a benign asymptomatic
condition.
(TPN) solutions and is never given intravenously as a source of carbohydrate. It has been suggested that excessive dietary intake of fructose may also result in reduced phosphorylation potential. However, this is still a contentious issue. Dietary fructose is not well absorbed and increased dietary intake often results in malabsorption. Whether or not sufficient amounts of dietary fructose could be absorbed to cause a significant reduction in phosphorylating potential in liver cells remains questionable and there are no clear examples of this in the literature.
Fructose
Fructose, or fruit sugar, is a simple monosaccharide found in many plants. It is one of the three dietary monosaccharides, along with glucose and galactose, that are absorbed directly into the bloodstream during digestion. Fructose was discovered by French chemist Augustin-Pierre Dubrunfaut in 1847...
from dietary sources. The metabolism of glucose
Glucose
Glucose is a simple sugar and an important carbohydrate in biology. Cells use it as the primary source of energy and a metabolic intermediate...
through glycolysis
Glycolysis
Glycolysis is the metabolic pathway that converts glucose C6H12O6, into pyruvate, CH3COCOO− + H+...
uses many of the same enzyme
Enzyme
Enzymes are proteins that catalyze chemical reactions. In enzymatic reactions, the molecules at the beginning of the process, called substrates, are converted into different molecules, called products. Almost all chemical reactions in a biological cell need enzymes in order to occur at rates...
s and intermediate structures as those in fructolysis, the two sugars have very different metabolic fates in human metabolism. Unlike glucose, which is metabolized widely in the body, fructose is metabolized almost completely in the liver in humans, where it is directed toward replenishment of liver glycogen
Glycogen
Glycogen is a molecule that serves as the secondary long-term energy storage in animal and fungal cells, with the primary energy stores being held in adipose tissue...
and triglyceride
Triglyceride
A triglyceride is an ester derived from glycerol and three fatty acids. There are many triglycerides, depending on the oil source, some are highly unsaturated, some less so....
synthesis.
Fructose is a dietary monosaccharide
Monosaccharide
Monosaccharides are the most basic units of biologically important carbohydrates. They are the simplest form of sugar and are usually colorless, water-soluble, crystalline solids. Some monosaccharides have a sweet taste. Examples of monosaccharides include glucose , fructose , galactose, xylose...
present naturally in fruit
Fruit
In broad terms, a fruit is a structure of a plant that contains its seeds.The term has different meanings dependent on context. In non-technical usage, such as food preparation, fruit normally means the fleshy seed-associated structures of certain plants that are sweet and edible in the raw state,...
s and vegetable
Vegetable
The noun vegetable usually means an edible plant or part of a plant other than a sweet fruit or seed. This typically means the leaf, stem, or root of a plant....
s, either as free fructose or as part of the disaccharide
Disaccharide
A disaccharide or biose is the carbohydrate formed when two monosaccharides undergo a condensation reaction which involves the elimination of a small molecule, such as water, from the functional groups only. Like monosaccharides, disaccharides form an aqueous solution when dissolved in water...
sucrose
Sucrose
Sucrose is the organic compound commonly known as table sugar and sometimes called saccharose. A white, odorless, crystalline powder with a sweet taste, it is best known for its role in human nutrition. The molecule is a disaccharide composed of glucose and fructose with the molecular formula...
, and as free monosaccharides in honey
Honey
Honey is a sweet food made by bees using nectar from flowers. The variety produced by honey bees is the one most commonly referred to and is the type of honey collected by beekeepers and consumed by humans...
. It is also present in the form of refined sugars including granulated sugars (white crystalline table sugar, brown sugar
Brown sugar
Brown sugar is a sucrose sugar product with a distinctive brown color due to the presence of molasses. It is either an unrefined or partially refined soft sugar consisting of sugar crystals with some residual molasses content, or it is produced by the addition of molasses to refined white...
, confectioner's sugar, and turbinado sugar), refined crystalline fructose
Fructose
Fructose, or fruit sugar, is a simple monosaccharide found in many plants. It is one of the three dietary monosaccharides, along with glucose and galactose, that are absorbed directly into the bloodstream during digestion. Fructose was discovered by French chemist Augustin-Pierre Dubrunfaut in 1847...
and as high fructose corn syrup
High fructose corn syrup
High-fructose corn syrup — also called glucose-fructose syrup in the UK, glucose/fructose in Canada, and high-fructose maize syrup in other countries — comprises any of a group of corn syrups that has undergone enzymatic processing to convert some of its glucose into fructose to produce...
s. Fructose represents about 20% of dietary carbohydrate
Carbohydrate
A carbohydrate is an organic compound with the empirical formula ; that is, consists only of carbon, hydrogen, and oxygen, with a hydrogen:oxygen atom ratio of 2:1 . However, there are exceptions to this. One common example would be deoxyribose, a component of DNA, which has the empirical...
intake (60 – 80 g) in most individuals. The typical American diet contains approximately 50% of the carbohydrate as polysaccharide
Polysaccharide
Polysaccharides are long carbohydrate molecules, of repeated monomer units joined together by glycosidic bonds. They range in structure from linear to highly branched. Polysaccharides are often quite heterogeneous, containing slight modifications of the repeating unit. Depending on the structure,...
s or starch
Starch
Starch or amylum is a carbohydrate consisting of a large number of glucose units joined together by glycosidic bonds. This polysaccharide is produced by all green plants as an energy store...
and approximately 50% as mono and disaccharides (sugars, both naturally occurring and refined).
Certain foods, such as apple
Apple
The apple is the pomaceous fruit of the apple tree, species Malus domestica in the rose family . It is one of the most widely cultivated tree fruits, and the most widely known of the many members of genus Malus that are used by humans. Apple grow on small, deciduous trees that blossom in the spring...
s and pear
Pear
The pear is any of several tree species of genus Pyrus and also the name of the pomaceous fruit of these trees. Several species of pear are valued by humans for their edible fruit, but the fruit of other species is small, hard, and astringent....
s, contain considerable amounts of free fructose relative to glucose. They are problematic in this regard, since the fructose (in excess of glucose) is not well absorbed and has been shown to cause osmotic
Osmosis
Osmosis is the movement of solvent molecules through a selectively permeable membrane into a region of higher solute concentration, aiming to equalize the solute concentrations on the two sides...
diarrhea
Diarrhea
Diarrhea , also spelled diarrhoea, is the condition of having three or more loose or liquid bowel movements per day. It is a common cause of death in developing countries and the second most common cause of infant deaths worldwide. The loss of fluids through diarrhea can cause dehydration and...
. The major consumers of apple juice are infants and children, and there are several published reports in the pediatric literature raising concern about the osmotic diarrhea and potential for dehydration
Dehydration
In physiology and medicine, dehydration is defined as the excessive loss of body fluid. It is literally the removal of water from an object; however, in physiological terms, it entails a deficiency of fluid within an organism...
, especially in infants.
Unlike glucose, fructose is not an insulin
Insulin
Insulin is a hormone central to regulating carbohydrate and fat metabolism in the body. Insulin causes cells in the liver, muscle, and fat tissue to take up glucose from the blood, storing it as glycogen in the liver and muscle....
secretagogue
Secretagogue
A secretagogue is a substance that causes another substance to be secreted. One example is gastrin,, which stimulates the H/K ATPase in the parietal cells...
. Fructose is also not metabolized in insulin-sensitive peripheral tissues. Fructose is selectively taken up and almost completely metabolized by liver hepatocyte
Hepatocyte
A hepatocyte is a cell of the main tissue of the liver. Hepatocytes make up 70-80% of the liver's cytoplasmic mass.These cells are involved in:* Protein synthesis* Protein storage* Transformation of carbohydrates...
s (the only other cells capable of metabolizing fructose, under normal conditions, are spermatozoa). Very little fructose escapes the liver, and fructose is not metabolized to any great extent in the small intestine, which lacks the fructose phosphorylating
Phosphorylation
Phosphorylation is the addition of a phosphate group to a protein or other organic molecule. Phosphorylation activates or deactivates many protein enzymes....
enzyme fructokinase
Fructokinase
Fructokinase , also known as D-fructokinase or D-fructose kinase, is an enzyme of the liver, intestine, and kidney cortex...
.
Fructolysis and Glycolysis are Independent Pathways
Although the metabolism of fructose and glucoseGlycolysis
Glycolysis is the metabolic pathway that converts glucose C6H12O6, into pyruvate, CH3COCOO− + H+...
share many of the same intermediate structures, they have very different metabolic fates in human metabolism. Fructose is metabolized almost completely in the liver in humans, and is directed toward replenishment of liver glycogen
Glycogen
Glycogen is a molecule that serves as the secondary long-term energy storage in animal and fungal cells, with the primary energy stores being held in adipose tissue...
and triglyceride
Triglyceride
A triglyceride is an ester derived from glycerol and three fatty acids. There are many triglycerides, depending on the oil source, some are highly unsaturated, some less so....
synthesis, while much of dietary glucose passes through the liver where it is metabolized in skeletal muscle to CO2, H2O and ATP
Adenosine triphosphate
Adenosine-5'-triphosphate is a multifunctional nucleoside triphosphate used in cells as a coenzyme. It is often called the "molecular unit of currency" of intracellular energy transfer. ATP transports chemical energy within cells for metabolism...
, and to fat cells where it is metabolized primarily to glycerol phosphate for triglyceride synthesis as well as energy production. The products of fructose metabolism are liver glycogen and de novo lipogenesis of fatty acids and eventual synthesis of endogenous triglyceride can be divided into two main phases: The first phase is the synthesis of the trioses, dihydroxyacetone
Dihydroxyacetone
Dihydroxyacetone , or DHA, also known as glycerone, is a simple carbohydrate with formula .DHA is primarily used as an ingredient in sunless tanning products. It is often derived from plant sources such as sugar beets and sugar cane, and by the fermentation of glycerin.-Chemistry:DHA is a...
(DHAP) and glyceraldehyde
Glyceraldehyde
Glyceraldehyde is a triose monosaccharide with chemical formula C3H6O3. It is the simplest of all common aldoses. It is a sweet, colorless, crystalline solid that is an intermediate compound in carbohydrate metabolism...
; the second phase is the subsequent metabolism of these trioses either in the gluconeogenic
Gluconeogenesis
Gluconeogenesis is a metabolic pathway that results in the generation of glucose from non-carbohydrate carbon substrates such as lactate, glycerol, and glucogenic amino acids....
pathway for glycogen replenishment and/or the complete metabolism in the fructolytic pathway to pyruvate
Pyruvic acid
Pyruvic acid is an organic acid, a ketone, as well as the simplest of the alpha-keto acids. The carboxylate ion of pyruvic acid, CH3COCOO−, is known as pyruvate, and is a key intersection in several metabolic pathways....
, which enters the Krebs cycle, is converted to citrate
Citrate
A citrate can refer either to the conjugate base of citric acid, , or to the esters of citric acid. An example of the former, a salt is trisodium citrate; an ester is triethyl citrate.-Other citric acid ions:...
and subsequently directed toward de novo synthesis of the free fatty acid palmitate
Palmitic acid
Palmitic acid, or hexadecanoic acid in IUPAC nomenclature, is one of the most common saturated fatty acids found in animals and plants. Its molecular formula is CH314CO2H. As its name indicates, it is a major component of the oil from palm trees . Palmitate is a term for the salts and esters of...
.
The Metabolism of Fructose to DHAP and Glyceraldehyde
The first step in the metabolism of fructose is the phosphorylation of fructose to fructose 1-phosphate by fructokinaseFructokinase
Fructokinase , also known as D-fructokinase or D-fructose kinase, is an enzyme of the liver, intestine, and kidney cortex...
(Km
Michaelis-Menten kinetics
In biochemistry, Michaelis–Menten kinetics is one of the simplest and best-known models of enzyme kinetics. It is named after German biochemist Leonor Michaelis and Canadian physician Maud Menten. The model takes the form of an equation describing the rate of enzymatic reactions, by relating...
= 0.5 mM, ≈ 9 mg/100 ml), thus trapping fructose for metabolism in the liver.Hexokinase IV
Hexokinase
A hexokinase is an enzyme that phosphorylates a six-carbon sugar, a hexose, to a hexose phosphate. In most tissues and organisms, glucose is the most important substrate of hexokinases, and glucose-6-phosphate the most important product....
(Glucokinase
Glucokinase
Glucokinase is an enzyme that facilitates phosphorylation of glucose to glucose-6-phosphate. Glucokinase occurs in cells in the liver, pancreas, gut, and brain of humans and most other vertebrates...
), also occurs in the liver and would be capable of phosphorylating fructose to fructose 6-phosphate
Fructose 6-phosphate
Fructose 6-phosphate is fructose sugar phosphorylated on carbon 6 . The β-D-form of this compound is very common in cells. The vast majority of glucose and fructose entering a cell will become converted to this at some point...
(an intermediate in the gluconeoenic
Gluconeogenesis
Gluconeogenesis is a metabolic pathway that results in the generation of glucose from non-carbohydrate carbon substrates such as lactate, glycerol, and glucogenic amino acids....
pathway); however, it has a relatively high Km (12 mM) for fructose and, therefore, essentially all of the fructose is converted to fructose-1-phosphate in the human liver. Much of the glucose, on the other hand, is not phosphorylated (Km of hepatic glucokinase (hexokinase IV) = 10 mM), passes through the liver directed toward peripheral tissues, and is taken up by the insulin-dependent glucose transporter, GLUT 4, present on adipose tissue
Adipose tissue
In histology, adipose tissue or body fat or fat depot or just fat is loose connective tissue composed of adipocytes. It is technically composed of roughly only 80% fat; fat in its solitary state exists in the liver and muscles. Adipose tissue is derived from lipoblasts...
and skeletal muscle.
Fructose-1-phosphate then undergoes hydrolysis by fructose-1-phosphate aldolase (aldolase B)
Aldolase B
Aldolase B also known as fructose-bisphosphate aldolase B or liver-type aldolase is one of three isoenzymes of the class I fructose 1,6-bisphosphate aldolase enzyme , and plays a key role in both glycolysis and gluconeogenesis...
to form dihydroxyacetone phosphate (DHAP) and glyceraldehyde; DHAP can either be isomerized to glyceraldehyde 3-phosphate by triosephosphate isomerase or undergo reduction to glycerol 3-phosphate by glycerol 3-phosphate dehydrogenase. The glyceraldehyde produced may also be converted to glyceraldehyde 3-phosphate by glyceraldehyde kinase or converted to glycerol 3-phosphate by glyceraldehyde 3-phosphate dehydrogenase. The metabolism of fructose at this point yields intermediates in gluconeogenic pathway leading to glycogen synthesis, or can be oxidized to pyruvate and reduced to lactate, or be decarboxylated to acetyl CoA in the mitochondria and directed toward the synthesis of free fatty acid, resulting finally in TG synthesis.
Figure 1 The Metabolic Conversion of Fructose to DHAP, Glyceraldehyde and Glyceraldehyde-3-Phosphate in the Liver
Synthesis of Glycogen from DHAP and Glyceraldehyde 3 Phosphate
The synthesis of glycogen in the liver following a fructose-containing meal proceeds from gluconeogenic precursors. Fructose is initially converted to DHAP and glyceraldehyde by fructokinase and aldolase B. The resultant glyceraldehyde then undergoes phosphorylation to glyceraldehyde-3-phosphate. Increased concentrations of DHAP and glyceraldehyde-3-phosphate in the liver drive the gluconeogenic pathway toward glucose-6-phosphate, glucose-1-phosphate and glycogen formation. It appears that fructose is a better substrate for glycogen synthesis than glucose and that glycogen replenishment takes precedence over triglyceride formation. Once liver glycogen is replenished, the intermediates of fructose metabolism are primarily directed toward triglyceride synthesis.Figure 2 The Metabolic Conversion of Fructose to Glycogen in the Liver
Synthesis of Triglyceride from DHAP and Glyceraldehyde-3-Phosphate
Carbons from dietary fructose are found in both the FFA and glycerol moieties of plasma TG. Excess dietary fructose can be converted to pyruvate, enter the Krebs cycleCitric acid cycle
The citric acid cycle — also known as the tricarboxylic acid cycle , the Krebs cycle, or the Szent-Györgyi-Krebs cycle — is a series of chemical reactions which is used by all aerobic living organisms to generate energy through the oxidization of acetate derived from carbohydrates, fats and...
and emerges as citrate
Citrate
A citrate can refer either to the conjugate base of citric acid, , or to the esters of citric acid. An example of the former, a salt is trisodium citrate; an ester is triethyl citrate.-Other citric acid ions:...
directed toward free fatty acid synthesis in the cytosol
Cytosol
The cytosol or intracellular fluid is the liquid found inside cells, that is separated into compartments by membranes. For example, the mitochondrial matrix separates the mitochondrion into compartments....
of hepatocytes. The DHAP formed during fructolysis can also be converted to glycerol and then glycerol 3-phosphate for TG synthesis. Thus, fructose can provide trioses for both the glycerol 3-phosphate backbone, as well as the free fatty acids in TG synthesis. Indeed, fructose may provide the bulk of the carbohydrate directed toward de novo TG synthesis in humans.
Figure 3 The Metabolic Conversion of Fructose to Triglyceride (TG) in the Liver
Fructose Induces Hepatic Lipogenic Enzymes
Fructose consumption results in the insulin-independent induction of several important hepatic lipogenic enzymes including pyruvate kinasePyruvate kinase
Pyruvate kinase is an enzyme involved in glycolysis. It catalyzes the transfer of a phosphate group from phosphoenolpyruvate to ADP, yielding one molecule of pyruvate and one molecule of ATP.-Reaction:The reaction with pyruvate kinase:...
, NADP+-dependent malate dehydrogenase
Malate dehydrogenase (NADP+)
In enzymology, a malate dehydrogenase is an enzyme that catalyzes the chemical reaction-malate + NADP+ \rightleftharpoons oxaloacetate + NADPH + H+...
, citrate lyase
ATP citrate lyase
ATP citrate lyase is an enzyme that represents an important step in fatty acid biosynthesis. This step in fatty acid biosynthesis occurs because ATP citrate lyase is the link between the metabolism of carbohydrates to the production of fatty acids.-Function:ATP citrate lyase is the primary enzyme...
, acetyl CoA carboxylase
Acetyl-CoA carboxylase
Acetyl-CoA carboxylase is a biotin-dependent enzyme that catalyzes the irreversible carboxylation of acetyl-CoA to produce malonyl-CoA through its two catalytic activities, biotin carboxylase and carboxyltransferase...
, fatty acid synthase
Fatty acid synthase
Fatty acid synthase is an enzyme that in humans is encoded by the FASN gene.Fatty acid synthase is a multi-enzyme protein that catalyzes fatty acid synthesis...
, as well as pyruvate dehydrogenase
Pyruvate dehydrogenase
Pyruvate dehydrogenase complex is a complex of three enzymes that transform pyruvate into acetyl-CoA by a process called pyruvate decarboxylation. Acetyl-CoA may then be used in the citric acid cycle to carry out cellular respiration, and this complex links the glycolysis metabolic pathway to the...
. Although not a consistent finding among metabolic feeding studies, high fructose diets have been shown to lead to hypertriglyceridemia
Hypertriglyceridemia
In medicine, hypertriglyceridemia denotes high blood levels of triglycerides, the most abundant fatty molecule in most organisms. It has been associated with atherosclerosis, even in the absence of hypercholesterolemia . It can also lead to pancreatitis in excessive concentrations In medicine,...
in a wide range of populations including individuals with normal glucose metabolism as well as individuals with impaired glucose tolerance, diabetes, hypertriglyceridemia, and hypertension. The hypertriglyceridemic effects observed are a hallmark of increased dietary carbohydrate, and fructose and appears to be dependent on a number of factors including the amount of dietary fructose consumed and degree insulin resistance
Insulin resistance
Insulin resistance is a physiological condition where the natural hormone insulin becomes less effective at lowering blood sugars. The resulting increase in blood glucose may raise levels outside the normal range and cause adverse health effects, depending on dietary conditions. Certain cell types...
.
Table 1 Hepatic Lipogenic Enzyme Activity ‡ in Control and Streptozotocin-Induced Diabetic Rats§ Follow a 14 day period with or without 25% Fructose Diet
| Group | Pyruvate Kinase | NADPH-Malate Dehydrogenase |
Citrate Lyase | Acetyl CoA Carboxylase |
Fatty Acid Synthase |
| Control Animals | |||||
| Control Diet | 495 ± 23 | 35 ± 5 | 21 ± 3 | 6.5 ± 1.0 | 3.6 ± 0.5 |
| Fructose Diet | 1380 ± 110* | 126 ± 9* | 69 ± 7* | 22.5 ± 2.7* | 10.8 ± 1.4* |
| Diabetic Animals | |||||
| Control Diet | 196 ± 21 | 14 ± 3 | 9 ± 2 | 3.1 ± 0.8 | 1.4 ± 0.6 |
| Fructose Diet | 648 ± 105* | 70 ± 9* | 37 ± 6* | 10.3 ± 2.0* | 3.9 ± 0.9* |
‡ = Mean ± SEM activity in nmol/min per mg protein
§ = 12 rats/group
- = Significantly different from control at p < 0.05
Shafrir, E. Fructose/Sucrose metabolism, its physiological and pathological implications. In Kretchmer, N. & Hollenbeck, CB. Sugars and Sweeteners, CRC Press, Boca Raton:FL, 1991.
Abnormalities in Fructose Metabolism
The lack of two important enzymes in fructose metabolism results in the development of two inborn errors in carbohydrate metabolism – essential fructosuriaEssential fructosuria
Essential fructosuria, also known as hepatic fructokinase deficiency or ketohexokinase deficiency, is a hereditary metabolic disorder caused by a deficiency in hepatic fructokinase, leading to fructose being excreted in the urine . It is essentially a benign condition, as fructose cannot be broken...
and hereditary fructose intolerance. In addition, reduced phosphorylation potential within hepatocytes can occur with intravenous infusion of fructose.
Essential Fructosuria
The absence of fructokinase results in the inability to phosphorylate fructose to fructose-1-phosphate within the cell. As a result, fructose is neither trapped within the cell nor directed toward its metabolism. Free fructose concentrations in the liver increase and fructose is free to leave the cell and enter plasma. This results in an increase in plasma concentration of fructose, eventually exceeding the renal threshold for fructose reabsorption resulting in the appearance of fructose in the urine. Essential fructosuriaEssential fructosuria
Essential fructosuria, also known as hepatic fructokinase deficiency or ketohexokinase deficiency, is a hereditary metabolic disorder caused by a deficiency in hepatic fructokinase, leading to fructose being excreted in the urine . It is essentially a benign condition, as fructose cannot be broken...
is a benign asymptomatic
Asymptomatic
In medicine, a disease is considered asymptomatic if a patient is a carrier for a disease or infection but experiences no symptoms. A condition might be asymptomatic if it fails to show the noticeable symptoms with which it is usually associated. Asymptomatic infections are also called subclinical...
condition.
Hereditary Fructose Intolerance
The absence of fructose-1-phosphate aldolase (aldolase B) results in the accumulation of fructose 1 phosphate in hepatocytes, kidney and small intestines. An accumulation of fructose-1-phosphate following fructose ingestion inhibits glycogenolysis (breakdown of glycogen) and gluconeogenesis, resulting in severe hypoglycemia. It is very symptomatic resulting in severe hypoglycemia, abdominal pain, vomiting, hemorrhage, jaundice, hepatomegaly, and hyperuricemia eventually leading to liver and/or renal failure and death. The incidence varies throughout the world, but is it estimated at about 1/20,000 (range 1/12,000 to 1/58,000) live births.Reduced Phosphorylation Potential
Intravenous (i.v.) infusion of fructose has been shown to lower phosphorylation potential in liver cells by trapping Pi as fructose 1-phosphate. The fructokinase reaction occurs quite rapidly in hepatocytes trapping fructose in cells by phosphorylation. On the other hand, the splitting of fructose 1 phosphate to DHAP and glyceraldehyde by Aldolase B is relatively slow. Therefore, fructose-1-phosphate accumulates with the corresponding reduction of intracellular Pi available for phosphorylation reactions in the cell. This is why fructose is contraindicated for total parenteral nutritionTotal parenteral nutrition
Parenteral nutrition is feeding a person intravenously, bypassing the usual process of eating and digestion. The person receives nutritional formulae that contain nutrients such as glucose, amino acids, lipids and added vitamins and dietary minerals...
(TPN) solutions and is never given intravenously as a source of carbohydrate. It has been suggested that excessive dietary intake of fructose may also result in reduced phosphorylation potential. However, this is still a contentious issue. Dietary fructose is not well absorbed and increased dietary intake often results in malabsorption. Whether or not sufficient amounts of dietary fructose could be absorbed to cause a significant reduction in phosphorylating potential in liver cells remains questionable and there are no clear examples of this in the literature.
External links
- The Entry of Fructose and Galactose into Glycolysis, Chapter 16.1.11. Biochemistry, 5th edition, Jeremy M Berg, John L Tymoczko, and Lubert Stryer, New York: W H Freeman; 2002.