When large amounts of fructose are ingested, the glycolytic pathway becomes saturated with intermediates. In these circumstances, the intermediates become substrates for triacylglycerol synthesis: DHAP can be converted to glycerol, and acetyl-CoA can enter the lipogenic pathway to form fatty acids that are then esterified to the glycerol molecule to form triacylglycerols. During the initial step of lipogenesis, malonyl-CoA is formed. This intermediate serves to inhibit the transport of fatty acids into the mitochondria, where they are oxidized. By this regulatory mechanism, esterification of the newly synthesized fatty acids is reinforced. Studies have shown that the ingestion of fructose results in increased synthesis of fatty acids compared to ingestion of a comparable amount of glucose. The increased availability of fatty acids and subsequent triacylglycerol synthesis results in the production and secretion of triacylglycerols from the liver in the form of very low-density lipoproteins. Studies in animals have demonstrated that when large quantities of fructose or sucrose are consumed, an increase in blood triacylglycerol concentration occurs. Similar findings have been observed in humans, although some humans appear to be more susceptible to fructose consumption than others. For example, the lipogenic sequence may be accentuated in humans with preexisting hypertriacylglycerolemia or in those who are insulin resistant. Since high circulating triacylglycerol levels have been identified as a risk factor for coronary heart disease, long-term exposure to high levels of dietary fructose may contribute to a chronic, unfavorable lipid profile and increase risk of coronary heart disease.
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