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bioRxiv · 10.1101/2024.05.22.595423

Excessive Dietary Fructose Aggravates Heart Failure via Impairing Myocardial Fatty Acid Oxidation Metabolism in Diet Induced Obese Mouse

Zhang, Y.·Xue, Y.·Gong, Q.·Zhu, M.·Li, J.·Xu, M.·Huang, H.
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Abstract

BackgroundAn unhealthy diet and a sedentary lifestyle increase the prevalence of cardiometabolic syndrome. Several cardiovascular diseases (CVDs) have been highly linked to excessive added sugar intake, which alters whole-body metabolism, including heart tissue. However, whether specific added sugars can cause and aggravate severe heart dysfunction is still unknown. MethodsWe examined the association between CVDs and added sugar intake using statistical analyses and Mendelian randomization (MR). Then, we evaluated the effect of added sugar on mouse heart function employing a diet-induced obese (DIO) model with transverse aortic constriction (TAC) challenge. We measured the fatty acid and fructose metabolic flux in mouse hearts employing a mass spectrometry-based in vivo double stable isotopic labeling (DSIL) technique. The results of animal models were also confirmed in aortic stenosis (AS) patient samples. ResultsStatistical analyses and MR estimation on public databases indicated that added sugars, especially fructose, are associated with a high risk of heart failure. Feeding on either ingested or drunk fructose could aggravate heart failure and diastolic and systolic dysfunction in TAC challenged DIO mice. Mechanistically, excessive dietary intake of fructose could suppress heart fatty acid oxidation (FAO) metabolism via both shrinkage of the flux rate of FAO and inhibition of the AMPK-ACC axis. Activation of AMPK or deactivation of ACC could limit such heart dysfunction and myocardial hypertrophy. We also obtained plasma from 27 patients with AS and determined that the high fructose level instead of glucose or sucrose was linked to left ventricular ejection fractions (LVEF) and fractional shortening (FS) decline. ConclusionsFindings from epidemiological statistical analyses and investigations of animal models suggested the harmful effect of excessive fructose intake on heart function. Fructose could directly alter heart metabolism by suppressing FAO. Our results implied that targeting AMPK-ACC mediation could effectively attenuate excessive fructose-induced heart failure in DIO mice.

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Zhang, Y., Xue, Y., Gong, Q., Zhu, M., Li, J., Xu, M., Huang, H.. 2024-05-25. Excessive Dietary Fructose Aggravates Heart Failure via Impairing Myocardial Fatty Acid Oxidation Metabolism in Diet Induced Obese Mouse. https://doi.org/10.1101/2024.05.22.595423

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