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Ketone body β-hydroxybutyrate is an autophagy-dependent vasodilator
Cameron G. McCarthy, … , Camilla F. Wenceslau, Bina Joe
Cameron G. McCarthy, … , Camilla F. Wenceslau, Bina Joe
Published September 9, 2021
Citation Information: JCI Insight. 2021;6(20):e149037. https://doi.org/10.1172/jci.insight.149037.
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Research Article Vascular biology

Ketone body β-hydroxybutyrate is an autophagy-dependent vasodilator

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Abstract

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.

Authors

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

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Figure 4

High-salt diet negatively regulates β-hydroxybutyrate synthesis and autophagic activity.

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High-salt diet negatively regulates β-hydroxybutyrate synthesis and auto...
β-Hydroxybutyrate (βHB) was measured in sera from nonfasted (free access to food) and fasted (24 hours) Dahl S and Dahl R rats that had consumed a low- or high-salt diet for 8 weeks (A). Protein expression analysis was performed for LC3B-II normalized to LC3B-I in liver biopsies from fasted and nonfasted low-salt diet– and high-salt diet–fed Dahl S and Dahl R rats (B). Representative images of immunoblots and densitometric analysis. Histological analysis was performed for fibrosis (C) and lipid droplets (D) in liver biopsies from nonfasted low-salt diet– and high-salt diet–fed Dahl S and Dahl R rats. Scale bar: 50 μm. Circulating liver enzymes (E and F), total cholesterol (G), triglycerides (H), and glucose (I) were measured in sera from nonfasted Dahl S and Dahl R rats that had consumed a low- or high-salt diet. Mean ± SEM. n = 4–10. Two-way ANOVA: *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001 (A and B); t test: *P < 0.05 (E–I).

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