Exercise Ameliorates Atherosclerosis via Up-Regulating Serum β-Hydroxybutyrate Levels

Zong-ze, XU; Zhang, Mingyue; Li, Xinran; Wang, Yong; Du, Ronghui

doi:10.3390/ijms23073788

Cited by 6 publications

(8 citation statements)

References 69 publications

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“…[20][21][22][23][24] β-HB, the most abundant ketone bodies, mainly produced in the liver, serves as a necessary alternative energy source when the body encounters an energy crisis, such as long periods of aerobic exercise. 25,26 Interestingly, accumulating evidence indicates an important role for β-HB in aerobic exercise-associated benefits, including atherosclerosis alleviation 29 and fat browning. 51 The present study elucidated that β-HB also functioned as the mediator for exercise-induced colitis amelioration, suggesting the diversity of "exercise/β-HB" pathway for health improvement.…”

Section: Discussionmentioning

confidence: 99%

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Exercise‐induced β‐hydroxybutyrate promotes Treg cell differentiation to ameliorate colitis in mice

Hao,

Tian,

Wang

et al. 2024

The FASEB Journal

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Increasing attention is being paid to the mechanistic investigation of exercise‐associated chronic inflammatory disease improvement. Ulcerative colitis (UC) is one type of chronic inflammatory bowel disease with increasing incidence and prevalence worldwide. It is known that regular moderate aerobic exercise (RMAE) reduces the incidence or risk of UC, and attenuates disease progression in UC patients. However, the mechanisms of this RMAE's benefit are still under investigation. Here, we revealed that β‐hydroxybutyrate (β‐HB), a metabolite upon prolonged aerobic exercise, could contribute to RMAE preconditioning in retarding dextran sulfate sodium (DSS)‐induced mouse colitis. When blocking β‐HB production, RMAE preconditioning‐induced colitis amelioration was compromised, whereas supplementation of β‐HB significantly rescued impaired β‐HB production‐associated defects. Meanwhile, we found that RMAE preconditioning significantly caused decreased colonic Th17/Treg ratio, which is considered to be important for colitis mitigation; and the downregulated Th17/Treg ratio was associated with β‐HB. We further demonstrated that β‐HB can directly promote the differentiation of Treg cell rather than inhibit Th17 cell generation. Furthermore, β‐HB increased forkhead box protein P3 (Foxp3) expression, the core transcriptional factor for Treg cell, by enhancing histone H3 acetylation in the promoter and conserved noncoding sequences of the Foxp3 locus. In addition, fatty acid oxidation, the key metabolic pathway required for Treg cell differentiation, was enhanced by β‐HB treatment. Lastly, administration of β‐HB without exercise significantly boosted colonic Treg cell and alleviated colitis in mice. Together, we unveiled a previously unappreciated role for exercise metabolite β‐HB in the promotion of Treg cell generation and RMAE preconditioning‐associated colitis attenuation.

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Section: Discussionmentioning

confidence: 99%

“…Exercise training was performed on a rodent treadmill as previously described 28,29 with minor modifications. In brief, mice assigned to RMAE were allowed to acclimatize themselves to the exercise for 1 week (adaptation period).…”

Section: Exercise Protocolmentioning

confidence: 99%

Exercise‐induced β‐hydroxybutyrate promotes Treg cell differentiation to ameliorate colitis in mice

Hao,

Tian,

Wang

et al. 2024

The FASEB Journal

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“… 195 Subsequent studies have revealed that in addition to histones, β-OHB can modify nonhistone proteins and participate in regulating diseases such as cancer and cardiometabolic diseases. 196 – 199 …”

Section: Principles and Mechanisms Of Protein Posttranslational Modif...mentioning

confidence: 99%

Targeting protein modifications in metabolic diseases: molecular mechanisms and targeted therapies

Geng

et al. 2023

Sig Transduct Target Ther

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The ever-increasing prevalence of noncommunicable diseases (NCDs) represents a major public health burden worldwide. The most common form of NCD is metabolic diseases, which affect people of all ages and usually manifest their pathobiology through life-threatening cardiovascular complications. A comprehensive understanding of the pathobiology of metabolic diseases will generate novel targets for improved therapies across the common metabolic spectrum. Protein posttranslational modification (PTM) is an important term that refers to biochemical modification of specific amino acid residues in target proteins, which immensely increases the functional diversity of the proteome. The range of PTMs includes phosphorylation, acetylation, methylation, ubiquitination, SUMOylation, neddylation, glycosylation, palmitoylation, myristoylation, prenylation, cholesterylation, glutathionylation, S-nitrosylation, sulfhydration, citrullination, ADP ribosylation, and several novel PTMs. Here, we offer a comprehensive review of PTMs and their roles in common metabolic diseases and pathological consequences, including diabetes, obesity, fatty liver diseases, hyperlipidemia, and atherosclerosis. Building upon this framework, we afford a through description of proteins and pathways involved in metabolic diseases by focusing on PTM-based protein modifications, showcase the pharmaceutical intervention of PTMs in preclinical studies and clinical trials, and offer future perspectives. Fundamental research defining the mechanisms whereby PTMs of proteins regulate metabolic diseases will open new avenues for therapeutic intervention.

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“…It has been reported that regular exercise can raise serum ketone body (β-OHB) levels, and this action has been suggested as a crucial mechanism of exercise halting the emergence of atherosclerosis [ 105 ]. Specifically, an experimental study showed that 3 months of habitual exercise on a treadmill considerably reduced lipid aggregation and formation of foam cells in ApoE −/− mice fed with a Western atherosclerotic diet [ 105 ]. This intervention increased β-OHB levels in the serum.…”

Section: Exercisementioning

confidence: 99%

Ketone Bodies and Cardiovascular Disease: An Alternate Fuel Source to the Rescue

Manolis

2023

IJMS

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The increased metabolic activity of the heart as a pump involves a high demand of mitochondrial adenosine triphosphate (ATP) production for its mechanical and electrical activities accomplished mainly via oxidative phosphorylation, supplying up to 95% of the necessary ATP production, with the rest attained by substrate-level phosphorylation in glycolysis. In the normal human heart, fatty acids provide the principal fuel (40–70%) for ATP generation, followed mainly by glucose (20–30%), and to a lesser degree (<5%) by other substrates (lactate, ketones, pyruvate and amino acids). Although ketones contribute 4–15% under normal situations, the rate of glucose use is drastically diminished in the hypertrophied and failing heart which switches to ketone bodies as an alternate fuel which are oxidized in lieu of glucose, and if adequately abundant, they reduce myocardial fat delivery and usage. Increasing cardiac ketone body oxidation appears beneficial in the context of heart failure (HF) and other pathological cardiovascular (CV) conditions. Also, an enhanced expression of genes crucial for ketone break down facilitates fat or ketone usage which averts or slows down HF, potentially by avoiding the use of glucose-derived carbon needed for anabolic processes. These issues of ketone body utilization in HF and other CV diseases are herein reviewed and pictorially illustrated.

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Exercise Ameliorates Atherosclerosis via Up-Regulating Serum β-Hydroxybutyrate Levels

Cited by 6 publications

References 69 publications

Exercise‐induced β‐hydroxybutyrate promotes Treg cell differentiation to ameliorate colitis in mice

Exercise‐induced β‐hydroxybutyrate promotes Treg cell differentiation to ameliorate colitis in mice

Targeting protein modifications in metabolic diseases: molecular mechanisms and targeted therapies

Ketone Bodies and Cardiovascular Disease: An Alternate Fuel Source to the Rescue

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