Journal article
Dietary ketone body–escalated histone acetylation in megakaryocytes alleviates chemotherapy-induced thrombocytopenia
Science translational medicine, Vol.14(673), pp.1-eabn9061
11/30/2022
DOI: 10.1126/scitranslmed.abn9061
Abstract
Chemotherapy-induced thrombocytopenia (CIT) is a severe complication in patients with cancer that can lead to impaired therapeutic outcome and survival. Clinically, therapeutic options for CIT are limited by severe adverse effects and high economic burdens. Here, we demonstrate that ketogenic diets alleviate CIT in both animals and humans without causing thrombocytosis. Mechanistically, ketogenic diet–induced circulating β-hydroxybutyrate (β-OHB) increased histone H3 acetylation in bone marrow megakaryocytes. Gain- and loss-of-function experiments revealed a distinct role of 3-β-hydroxybutyrate dehydrogenase (BDH)–mediated ketone body metabolism in promoting histone acetylation, which promoted the transcription of platelet biogenesis genes and induced thrombocytopoiesis. Genetic depletion of the megakaryocyte-specific ketone body transporter monocarboxylate transporter 1 (MCT1) or pharmacological targeting of MCT1 blocked β-OHB–induced thrombocytopoiesis in mice. A ketogenesis-promoting diet alleviated CIT in mouse models. Moreover, a ketogenic diet modestly increased platelet counts without causing thrombocytosis in healthy volunteers, and a ketogenic lifestyle inversely correlated with CIT in patients with cancer. Together, we provide mechanistic insights into a ketone body–MCT1–BDH–histone acetylation–platelet biogenesis axis in megakaryocytes and propose a nontoxic, low-cost dietary intervention for combating CIT.
Details
- Title: Subtitle
- Dietary ketone body–escalated histone acetylation in megakaryocytes alleviates chemotherapy-induced thrombocytopenia
- Creators
- Sisi XieChenyu JiangMeng WuYing YeBiying WuXiaoting SunXue LvRuibo ChenWen YuQi SunYuting WuRongliang QueHuilan LiLing YangWen LiuJi ZuoLasse JensenGuichun HuangYihai CaoYunlong Yang
- Resource Type
- Journal article
- Publication Details
- Science translational medicine, Vol.14(673), pp.1-eabn9061
- Publisher
- The American Association for the Advancement of Science
- DOI
- 10.1126/scitranslmed.abn9061
- ISSN
- 1946-6234
- eISSN
- 1946-6242
- Language
- English
- Date published
- 11/30/2022
- Academic Unit
- Pharmacy; Molecular Physiology and Biophysics; Fraternal Order of Eagles Diabetes Research Center; Anatomy and Cell Biology
- Record Identifier
- 9984321947502771
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