Ketone body β-hydroxybutyrate is an autophagy-dependent vasodilator
Autophagy has long been associated with longevity, and it is well established that autophagy reverts and prevents vascular deterioration associated with aging and cardiovascular diseases. Currently, our understanding of how autophagy benefits the vasculature is centered on the premise that reduced a...
| Main Authors: | , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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American Society for Clinical investigation
2021-10-01
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| Series: | JCI Insight |
| Subjects: | |
| Online Access: | https://doi.org/10.1172/jci.insight.149037 |
| _version_ | 1811226971886059520 |
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| author | Cameron G. McCarthy Saroj Chakraborty Gagandeep Singh Beng San Yeoh Zachary J. Schreckenberger Avinash Singh Blair Mell Nicole R. Bearss Tao Yang Xi Cheng Matam Vijay-Kumar Camilla F. Wenceslau Bina Joe |
| author_facet | Cameron G. McCarthy Saroj Chakraborty Gagandeep Singh Beng San Yeoh Zachary J. Schreckenberger Avinash Singh Blair Mell Nicole R. Bearss Tao Yang Xi Cheng Matam Vijay-Kumar Camilla F. Wenceslau Bina Joe |
| author_sort | Cameron G. McCarthy |
| collection | DOAJ |
| description | Autophagy has long been associated with longevity, and it is well established that autophagy reverts and prevents vascular deterioration associated with aging and cardiovascular diseases. Currently, our understanding of how autophagy benefits the vasculature is centered on the premise that reduced autophagy leads to the accumulation of cellular debris, resulting in inflammation and oxidative stress, which are then reversed by reconstitution or upregulation of autophagic activity. Evolutionarily, autophagy also functions to mobilize endogenous nutrients in response to starvation. Therefore, we hypothesized that the biosynthesis of the most physiologically abundant ketone body, β-hydroxybutyrate (βHB), would be autophagy dependent and exert vasodilatory effects via its canonical receptor, Gpr109a. To the best of our knowledge, we have revealed for the first time that the biosynthesis of βHB can be impaired by preventing autophagy. Subsequently, βHB caused potent vasodilation via potassium channels but not Gpr109a. Finally, we observed that chronic consumption of a high-salt diet negatively regulates both βHB biosynthesis and hepatic autophagy and that reconstitution of βHB bioavailability prevents high-salt diet–induced endothelial dysfunction. In summary, this work offers an alternative mechanism to the antiinflammatory and antioxidative stress hypothesis of autophagy-dependent vasculoprotection. Furthermore, it reveals a direct mechanism by which ketogenic interventions (e.g., intermittent fasting) improve vascular health. |
| first_indexed | 2024-04-12T09:33:36Z |
| format | Article |
| id | doaj.art-763a5fbdaf5b432c91d5fd854496b7c2 |
| institution | Directory Open Access Journal |
| issn | 2379-3708 |
| language | English |
| last_indexed | 2024-04-12T09:33:36Z |
| publishDate | 2021-10-01 |
| publisher | American Society for Clinical investigation |
| record_format | Article |
| series | JCI Insight |
| spelling | doaj.art-763a5fbdaf5b432c91d5fd854496b7c22022-12-22T03:38:17ZengAmerican Society for Clinical investigationJCI Insight2379-37082021-10-01620Ketone body β-hydroxybutyrate is an autophagy-dependent vasodilatorCameron G. McCarthySaroj ChakrabortyGagandeep SinghBeng San YeohZachary J. SchreckenbergerAvinash SinghBlair MellNicole R. BearssTao YangXi ChengMatam Vijay-KumarCamilla F. WenceslauBina JoeAutophagy has long been associated with longevity, and it is well established that autophagy reverts and prevents vascular deterioration associated with aging and cardiovascular diseases. Currently, our understanding of how autophagy benefits the vasculature is centered on the premise that reduced autophagy leads to the accumulation of cellular debris, resulting in inflammation and oxidative stress, which are then reversed by reconstitution or upregulation of autophagic activity. Evolutionarily, autophagy also functions to mobilize endogenous nutrients in response to starvation. Therefore, we hypothesized that the biosynthesis of the most physiologically abundant ketone body, β-hydroxybutyrate (βHB), would be autophagy dependent and exert vasodilatory effects via its canonical receptor, Gpr109a. To the best of our knowledge, we have revealed for the first time that the biosynthesis of βHB can be impaired by preventing autophagy. Subsequently, βHB caused potent vasodilation via potassium channels but not Gpr109a. Finally, we observed that chronic consumption of a high-salt diet negatively regulates both βHB biosynthesis and hepatic autophagy and that reconstitution of βHB bioavailability prevents high-salt diet–induced endothelial dysfunction. In summary, this work offers an alternative mechanism to the antiinflammatory and antioxidative stress hypothesis of autophagy-dependent vasculoprotection. Furthermore, it reveals a direct mechanism by which ketogenic interventions (e.g., intermittent fasting) improve vascular health.https://doi.org/10.1172/jci.insight.149037Vascular biology |
| spellingShingle | Cameron G. McCarthy Saroj Chakraborty Gagandeep Singh Beng San Yeoh Zachary J. Schreckenberger Avinash Singh Blair Mell Nicole R. Bearss Tao Yang Xi Cheng Matam Vijay-Kumar Camilla F. Wenceslau Bina Joe Ketone body β-hydroxybutyrate is an autophagy-dependent vasodilator JCI Insight Vascular biology |
| title | Ketone body β-hydroxybutyrate is an autophagy-dependent vasodilator |
| title_full | Ketone body β-hydroxybutyrate is an autophagy-dependent vasodilator |
| title_fullStr | Ketone body β-hydroxybutyrate is an autophagy-dependent vasodilator |
| title_full_unstemmed | Ketone body β-hydroxybutyrate is an autophagy-dependent vasodilator |
| title_short | Ketone body β-hydroxybutyrate is an autophagy-dependent vasodilator |
| title_sort | ketone body β hydroxybutyrate is an autophagy dependent vasodilator |
| topic | Vascular biology |
| url | https://doi.org/10.1172/jci.insight.149037 |
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