Fructose Metabolism and Cardiac Metabolic Stress

Abstract

Cardiovascular disease is one of the leading causes of mortality in diabetes. High fructose consumption has been linked with the development of diabetes and cardiovascular disease. Serum and cardiac tissue fructose levels are elevated in diabetic patients, and cardiac production of fructose via the intracellular polyol pathway is upregulated. The question of whether direct myocardial fructose exposure and upregulated fructose metabolism have potential to induce cardiac fructose toxicity in metabolic stress settings arises. Unlike tightly-regulated glucose metabolism, fructose bypasses the rate-limiting glycolytic enzyme, phosphofructokinase, and proceeds through glycolysis in an unregulated manner. In vivo rodent studies have shown that high dietary fructose induces cardiac metabolic stress and functional disturbance. In vitro, studies have demonstrated that cardiomyocytes cultured in high fructose exhibit lipid accumulation, inflammation, hypertrophy and low viability. Intracellular fructose mediates post-translational modification of proteins, and this activity provides an important mechanistic pathway for fructose-related cardiomyocyte signaling and functional effect. Additionally, fructose has been shown to provide a fuel source for the stressed myocardium. Elucidating the mechanisms of fructose toxicity in the heart may have important implications for understanding cardiac pathology in metabolic stress settings.

Moderate- and High-Intensity Endurance Training Alleviate Diabetes-Induced Cardiac Dysfunction in Rats

“…This observed trend is largely driven by modifiable lifestyle factors, including insufficient physical activity and an unhealthy diet [ 3 ]. An essential dietary determinant of T2DM is the increased consumption of refined sugars, in the form of glucose, fructose and sucrose, used extensively in the food industry [ 4 , 5 ]. Cohort studies have demonstrated an association between sugar-sweetened beverages and foods and the incidence of T2DM and diabetes-related comorbidities, including cardiovascular diseases (CVD) [ 6 , 7 , 8 , 9 ].…”

Acute Intake of Fructose Increases Arterial Pressure in Humans: A Meta-Analysis and Systematic Review

“…In contrast, despite comparable caloric intake and weight gain, the consumption of glucose-sweetened beverages over a 10-week period does not increase visceral adiposity [ 76 ]. In addition, fructose promotes inflammation and lipid accumulation in cardiac myocytes and enhances myocardial and vascular superoxide generation [ 77 , 78 ]. Together, these mechanisms conspire to promote hypertension and adverse cardiovascular effects.…”

Molecular mechanisms of metabolic dysregulation in diabetic cardiomyopathy

“…Dietary intake is the main extracellular source of fructose, which enters the cardiomyocytes via the systemic circulation. The intracellular source is the polyol pathway, wherein glucose is reduced to sorbitol by aldose reductase and sorbitol is then oxidized to fructose by sorbitol dehydrogenase (SDH) ( 14 ).…”

“…Fructose exposure is associated with metabolic disorders, lipid accumulation, inflammation, and apoptosis ( 108 , 109 ). Increased cellular fructose metabolism promotes the formation of O-Glcnacylation and AGEs, which are crucial for fructose-mediated cardiomyocyte signaling and dysfunction ( 13 , 14 ).…”

“…Some review articles, such as those written by Ding An and his colleagues, have summarized that dysregulation of glucose and lipid metabolism causes changes in cardiometabolism, which leads to mitochondrial dysfunction and impaired cardiac function ( 12 ). In addition to FA and glucose, energy can be generated using other substrates, such as fructose ( 13 , 14 ), lactate ( 15 ), amino acids ( 16 ), and ketone bodies ( 17 ), in the heart. The metabolic imbalance of these fuels is also linked to the occurrence and development of DCM ( Figure 1 ).…”