User talk:Pippin2k
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CHEMENG283 Wiki Project: Biochemical mechanisms of fructose toxicity
Evolutionary background
Excessive consumption of fructose-rich foods has been suggested to contribute to negative health outcomes.[1][2][3] Unlike glucose, whose metabolism is more rigorously controlled by the PFK1 enzyme, fructose is regulated and processed through metabolic pathways in a less complex manner. Fructokinase, the enzyme that activates fructose intracellularly via phosphorylation to commence its utilization, is not subject to negative feedback control from the downstream intermediates of glycolysis, the TCA cycle, or energy carriers.[4][5][6] This can result in large amounts of acetyl-CoA originating from the metabolism of fructose being fed into fatty acid biosynthesis pathways.[7][8] This increased flux through the fatty acid pathways results in highly elevated generation and accumulation rates for various fats. In some hibernating mammals, it is suggested that this deregulated utilization of fructose might have an advantageous adaptive role.[9] Rapid generation of fat storage when animals feed before the winter on seasonal ripe fruits, which are high in fructose, allows them to build a significant energy storage in a short time period. In some animals that are native to locations with pronounced seasonality, this mechanism also can contribute to fat accumulation to increase robustness and survive resource-scarce winters.[10] It is argued that this mechanism is also present in primates, including humans. Furthermore, its residual effects may cause more harm than benefit as hibernation is not a selective pressure in modern society and human metabolism has not evolved to handle excessive caloric/carbohydrate intake.[5][10]
Biochemical mechanisms
Moderate fruit consumption does not usually increase the blood levels of fructose since the small intestine uses it to generate glucose. [11] However, when fructose is artificially added in foods or when excessive amounts of fructose or sucrose-rich fruit is consumed, it can noticeably reach the systemic circulation.[12] The systemic bioavailability of fructose is positively correlated with increased de novo lipogenesis, decreased fatty acid oxidation, increased liver fat, postprandial triglycerides, cholesterol, low-density lipoprotein (LDL), high-density lipoprotein (HDL)-C, and C-reactive protein. These effects are substantially more pronounced in regards to fructose consumption when compared to excessive glucose intake.[13] Moreover, the lipogenic effects of fructose are exacerbated with the associated uptake of saturated fatty acids.[14] This compounding effect is quite likely fueled by diets containing fast foods that are both highly sweetened and processed in oils or high in fat.[15]
Fructose metabolism intermediates can also activate the glycolytic pathway by entering through glyceraldehyde-3-phosphate and dihydroxyacetone phosphate, which could be especially detrimental in cancer due to the Warburg effect.[16] Transient intracellular phosphate depletion due to the excessive phosphorylation of fructose by fructokinase may also affect purine metabolism resulting in increased production of uric acid. Uric acid, in turn, may further promote lipogenesis, as well as mediate other pathological processes that play an important role in the development of metabolic syndrome, high blood pressure, and gout.[17] Negative metabolic effects of fructose are compounded by its inability, unlike glucose, to induce satiety. This may be the reason for less controlled or excessive consumption of fructose-rich foods.[18]
Inhibition of fructose metabolism
Hereditary fructokinase deficiency does not appear to have any apparent negative health effects in humans[19] and may actually be associated with a better prognosis in populations where diets include large amounts of fructose.[20] It is possible that without normal fructokinase activity, metabolism of exogenous fructose would be decreased since fructose metabolites would be able to neither feed in acetyl-CoA generation nor upregulate lipid synthesis and accumulation. The excessive amount of fructose will simply be excreted with urine resulting in fructosuria, which is virtually a harmless health condition that could be incidentally found during a medical check-up for unrelated reasons.[21] It is shown that fructokinase inhibition might also be beneficial in ischemic acute kidney injury since, under this condition, fructose mediates oxidative stress and cell injury.[22][23] It is suggested that preventing or decreasing the metabolism of exogenous fructose will be beneficial in terms of carbohydrate and lipid metabolism as well as will decrease uric acid production which is beneficial as increased uric acid buildup triggers oxidative stress and inflammation.[24] Luteolin, an ingredient in some dietary supplements, was used in animal studies to inhibit fructose metabolism and showed beneficial effects in disrupting pathological processes mediated by fructose. However, the clinical relevance of these findings for humans is not known.[25]
