2021
DOI: 10.1038/s41392-020-00411-4
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Ketogenic diets inhibit mitochondrial biogenesis and induce cardiac fibrosis

Abstract: In addition to their use in relieving the symptoms of various diseases, ketogenic diets (KDs) have also been adopted by healthy individuals to prevent being overweight. Herein, we reported that prolonged KD exposure induced cardiac fibrosis. In rats, KD or frequent deep fasting decreased mitochondrial biogenesis, reduced cell respiration, and increased cardiomyocyte apoptosis and cardiac fibrosis. Mechanistically, increased levels of the ketone body β-hydroxybutyrate (β-OHB), an HDAC2 inhibitor, promoted histo… Show more

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Cited by 123 publications
(72 citation statements)
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“…One study reported that prolonged exposure to β-OHB had a detrimental effect on cardiomyocytes by altering glucose uptake and increasing ROS production via inhibiting the activation of AMPK/p38 MAPK signaling pathway (Pelletier and Coderre, 2007). This was also confirmed by other studies demonstrating that a prolonged exposure to β-OHB induced by deep fasting or frequent exogenous supplementation can inhibit mitochondrial biogenesis and lead to atrial fibrosis by activating Sirtuin 7 (Sirt7) transcription through inhibiting histone deacetylases 2 (HDAC2) (Xu et al, 2021). We have summarized the discrepancies of these studies in Supplementary Table S1, which underscores the importance of the timing and concentration of β-OHB given in different heart disease models, i.e., I/R injury, pressure-overload, diabetic cardiomyopathy.…”
Section: β-Ohb Is Cardioprotective In Animal Modelsmentioning
confidence: 74%
See 1 more Smart Citation
“…One study reported that prolonged exposure to β-OHB had a detrimental effect on cardiomyocytes by altering glucose uptake and increasing ROS production via inhibiting the activation of AMPK/p38 MAPK signaling pathway (Pelletier and Coderre, 2007). This was also confirmed by other studies demonstrating that a prolonged exposure to β-OHB induced by deep fasting or frequent exogenous supplementation can inhibit mitochondrial biogenesis and lead to atrial fibrosis by activating Sirtuin 7 (Sirt7) transcription through inhibiting histone deacetylases 2 (HDAC2) (Xu et al, 2021). We have summarized the discrepancies of these studies in Supplementary Table S1, which underscores the importance of the timing and concentration of β-OHB given in different heart disease models, i.e., I/R injury, pressure-overload, diabetic cardiomyopathy.…”
Section: β-Ohb Is Cardioprotective In Animal Modelsmentioning
confidence: 74%
“…Although fasting-induced β-OHB is cardioprotective, a ketogenic diet with high-fat content might be detrimental in the long term. At least in rodents, a long-term ketogenic diet decreased sensitivity to peripheral insulin, impaired glucose tolerance (Kinzig et al, 2010), and induced atrial fibrosis (Xu et al, 2021). Thus, the intermittent fasting-mimicking diet cycles might be a promising lifestyle intervention to induce protective ketosis of β-OHB.…”
Section: β-Ohb Is Cardioprotective In Humansmentioning
confidence: 99%
“…Unfortunately, the extreme composition of ketogenic diets makes it non-palatable and difficult to tolerate by many patients, who develop gastrointestinal complications (Cai et al, 2017), ultimately compromising compliance. In addition, recent studies have alerted of potential side effects (Cai et al, 2017), including an increase in serum lipidemia with concomitant increased risk of cardiovascular alterations (Zamani et al, 2016), higher risk of bone mass reduction (Simm et al, 2017), long-term alterations in the immune system (Goldberg et al, 2020), or increased probabilities for cardiac fibrosis (Xu et al, 2021). Because of these potential adverse effects, and the difficulty to adhere to the diet, different dietary formulations are being proposed to achieve a therapeutic effect with a more tolerable nutritional intervention (Dallérac et al, 2017;Kossoff and Cervenka, 2020).…”
Section: Discussionmentioning
confidence: 99%
“…Increased serum KB levels were independently associated with cardiovascular events and all-cause death in patients receiving hemodialysis [26]. A recently published study reported that prolonged KD exposure induces cardiac fibrosis [27]. In rats, KD or frequent deep fasting decreased mitochondrial biogenesis, reduced cell respiration, and increased cardiomyocyte apoptosis and cardiac fibrosis.…”
Section: Limitations and Potential Side Effects Of A Ketogenic Dietmentioning
confidence: 98%