Ketogenic diet attenuates aging-associated myocardial remodeling and dysfunction in mice

Yu, Yunhua; Wang, Fei; Wang, Jianjun; Zhang, Dongmei; Zhao, Xianxian

doi:10.1016/j.exger.2020.111058

Cited by 26 publications

(15 citation statements)

References 39 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…CHOP, a key apoptosis-promoting factor, tightly controls the gene transcription and has pivotal roles in lipid accumulation, adipogenesis and in ammatory action (Liu et al 2018;Maris et al 2012;Allagnat et al 2012). And one report has showed that KD intervention in mice could reduce the expression of CHOP (Yu et al 2020), which is consistent to our current study. In addition, it has also been proposed that SREBP-1c binds to its lipogenic target genes, such as fatty acid synthase (FASN) and stearoyl-CoA desaturase 1 (SCD1), thereby stimulating de novo lipogenesis (Li et al 2015).…”

Section: Discussionsupporting

confidence: 91%

Ketogenic Diet Ameliorates Lipid Dysregulation in Type 2 Diabetic Mice by Downregulating Hepatic Pescadillo 1

Zhou

Lü

Jia

et al. 2021

Preprint

View full text Add to dashboard Cite

Background: Previous reports implied a possible link between PES1 and lipid metabolism. However, the role of PES1 in regulation of T2DM related lipid metabolism and the effect of KD on PES1 have not been reported. The aim of present study is to explore the role of PES1 in effects of ketogenic diet (KD) on diabetic mice and its mediated mechanism.Methods: Male C57BL/6J and KKAy mice were fed with standard diet (SD) and KD, respectively. Simultaneously, McArdle 7777 cells were treated by β-hydroxybutyric acid (β-HB), Pes1 siRNA or Pes1 overexpression plasmid, respectively. Additionally, liver-conditional knockout (CKO) of Pes1 in vivo were used.Results: We unexpectedly found that hepatic PES1 expression in T2DM patients was markedly elevated, but the elevated PES1 was suppressed by KD feeding in T2DM mice with the reduction of hepatic and plasma triglycerides (TG). In mice with CKO of Pes1, the protein levels of p300, SREBP1c, FASN, SCD1, caspase1, NLRP3 and GSDMD were dramatically downregulated in livers, and the plasma and hepatic TG, IL-1β and IL-18 were decreased as well. The similar phenomena were also observed in β-HB and Pes1 knockdown treated hepatocytes. By contrast, Pes1 overexpression in cultured hepatocytes showed that these levels were significantly enhanced, which however were reduced under β-HB treatment. Mechanistically, we discovered that β-HB decreased CHOP binding to the Pes1 promoters, resulting in the downregulation of PES1, thereby reducing PES1 binding to p300 and caspase1 promoters. The inhibition of p300 and caspase1 expressions elicited the dramatic suppression of acetylation of SREBP1c via its interaction with p300, and the decreased GSDMD levels. Besides, knockdown of caspase1 also alleviated the TG levels in cultured hepatocytes.Conclusion: KD may improve lipid dysregulation in type 2 diabetic mice by downregulating hepatic PES1 expression.

show abstract

Section: Discussionsupporting

confidence: 91%

Ketogenic Diet Ameliorates Lipid Dysregulation in Type 2 Diabetic Mice by Downregulating Hepatic Pescadillo 1

Zhou

Lü

Jia

et al. 2021

Preprint

View full text Add to dashboard Cite

show abstract

“…Ketone bodies have emerged as beneficial nutrients in cardiac pathophysiology. A modest increase in circulating ketone bodies resulting from ketogenic diet consumption mitigates oxidative stress in the heart, as evidenced by decreases in oxidized glutathione, 3-nitrotyrosine, and malondialdehyde levels [20]. The current study shows that βHB at 0.3-3 mM upregulates Trx1 and confers resistance against oxidative stress through Trx1 in cultured cardiomyocytes.…”

Section: βHb Upregulates Trx1supporting

confidence: 49%

β-Hydroxybutyrate, a Ketone Body, Potentiates the Antioxidant Defense via Thioredoxin 1 Upregulation in Cardiomyocytes

et al. 2021

View full text Add to dashboard Cite

Thioredoxin 1 (Trx1) is a major antioxidant that acts adaptively to protect the heart during the development of diabetic cardiomyopathy. The molecular mechanism(s) responsible for regulating the Trx1 level and/or activity during diabetic cardiomyopathy is unknown. β-hydroxybutyrate (βHB), a major ketone body in mammals, acts as an alternative energy source in cardiomyocytes under stress, but it also appears to be involved in additional mechanisms that protect the heart against stress. βHB upregulated Trx1 in primary cultured cardiomyocytes in a dose- and a time-dependent manner and a ketogenic diet upregulated Trx1 in the heart. βHB protected cardiomyocytes against H2O2-induced death, an effect that was abolished in the presence of Trx1 knockdown. βHB also alleviated the H2O2-induced inhibition of mTOR and AMPK, known targets of Trx1, in a Trx1-dependent manner, suggesting that βHB potentiates Trx1 function. It has been shown that βHB is a natural inhibitor of HDAC1 and knockdown of HDAC1 upregulated Trx1 in cardiomyocytes, suggesting that βHB may upregulate Trx1 through HDAC inhibition. βHB induced Trx1 acetylation and inhibited Trx1 degradation, suggesting that βHB-induced inhibition of HDAC1 may stabilize Trx1 through protein acetylation. These results suggest that βHB potentiates the antioxidant defense in cardiomyocytes through the inhibition of HDAC1 and the increased acetylation and consequent stabilization of Trx1. Thus, modest upregulation of ketone bodies in diabetic hearts may protect the heart through the upregulation of Trx1.

show abstract

“…Other studies reported both beneficial and detrimental effects of KD on the heart [5,6]. In vitro study showed an unflavored role of KD in cardiac fibroblast activation [6] and prevention of cardiomyocyte loss [5]. Besides, KD is also found to be related to live fibrosis [31].…”

Section: Discussionmentioning

confidence: 98%

“…Thus, the influence of therapeutic duration could not be neglected since KD could correct metabolic dysfunction, which may confound its intrinsic effects on the heart and lon-ger time may be needed to investigate the real and long-time effects of KD. Other studies reported both beneficial and detrimental effects of KD on the heart [5,6]. In vitro study showed an unflavored role of KD in cardiac fibroblast activation [6] and prevention of cardiomyocyte loss [5].…”

Section: Discussionmentioning

confidence: 98%

“…However, on the other hand, it has been linked to vascular insult recently [3]. In the field of cardiac remodeling, KD is reported to be associated with improved cardiac function, cardiomyocyte survival, and attenuated cardiac fibrosis in both T2DM and aging mice [4,5]. In contrast, ketogenic diet was shown to be associated with cardiac remodeling in hypertensive rats [6].…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Ketogenic Diet Suppressed T‐Regulatory Cells and Promoted Cardiac Fibrosis via Reducing Mitochondria‐Associated Membranes and Inhibiting Mitochondrial Function

Tao

Chen

Wang

et al. 2021

Oxidative Medicine and Cellular Longevity

View full text Add to dashboard Cite

Ketogenic diet (KD) is popular in diabetic patients but its cardiac safety and efficiency on the heart are unknown. The aim of the present study is to determine the effects and the underlined mechanisms of KD on cardiac function in diabetic cardiomyopathy (DCM). We used db/db mice to model DCM, and different diets (regular or KD) were used. Cardiac function and interstitial fibrosis were determined. T-regulatory cell (Treg) number and functions were evaluated. The effects of ketone body (KB) on fatty acid (FA) and glucose metabolism, mitochondria-associated endoplasmic reticulum membranes (MAMs), and mitochondrial respiration were assessed. The mechanisms via which KB regulated MAMs and Tregs were addressed. KD improved metabolic indices in db/db mice. However, KD impaired cardiac diastolic function and exacerbated ventricular fibrosis. Proportions of circulatory CD4+CD25+Foxp3+ cells in whole blood cells and serum levels of IL-4 and IL-10 were reduced in mice fed with KD. KB suppressed the differentiation to Tregs from naive CD4+ T cells. Cultured medium from KB-treated Tregs synergically activated cardiac fibroblasts. Meanwhile, KB inhibited Treg proliferation and productions of IL-4 and IL-10. Treg MAMs, mitochondrial respiration and respiratory complexes, and FA synthesis and oxidation were all suppressed by KB while glycolytic levels were increased. L-carnitine reversed Treg proliferation and function inhibited by KB. Proportions of ST2L+ cells in Tregs were reduced by KB, as well as the production of ST2L ligand, IL-33. Reinforcement expressions of ST2L in Tregs counteracted the reductions in MAMs, mitochondrial respiration, and Treg proliferations and productions of Treg cytokines IL-4 and IL-10. Therefore, despite the improvement of metabolic indices, KD impaired Treg expansion and function and promoted cardiac fibroblast activation and interstitial fibrosis. This could be mainly mediated by the suppression of MAMs and fatty acid metabolism inhibition via blunting IL-33/ST2L signaling.

show abstract

Ketogenic diet attenuates aging-associated myocardial remodeling and dysfunction in mice

Cited by 26 publications

References 39 publications

Ketogenic Diet Ameliorates Lipid Dysregulation in Type 2 Diabetic Mice by Downregulating Hepatic Pescadillo 1

Ketogenic Diet Ameliorates Lipid Dysregulation in Type 2 Diabetic Mice by Downregulating Hepatic Pescadillo 1

β-Hydroxybutyrate, a Ketone Body, Potentiates the Antioxidant Defense via Thioredoxin 1 Upregulation in Cardiomyocytes

Ketogenic Diet Suppressed T‐Regulatory Cells and Promoted Cardiac Fibrosis via Reducing Mitochondria‐Associated Membranes and Inhibiting Mitochondrial Function

Contact Info

Product

Resources

About