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Abstract Atherosclerosis is a chronic inflammatory disease that can cause acute cardiovascular events. Activation of the NOD‐like receptor family, pyrin domain containing protein 3 (NLRP3) inflammasome enhances atherogenesis, which links lipid metabolism to sterile inflammation. This study examines the impact of an endogenous metabolite, namely ketone body 3‐hydroxybutyrate (3‐HB), on a mouse model of atherosclerosis. It is found that daily oral administration of 3‐HB can significantly ameliorate atherosclerosis. Mechanistically, 3‐HB is found to reduce the M1 macrophage proportion and promote cholesterol efflux by acting on macrophages through its receptor G‐protein‐coupled receptor 109a (Gpr109a). 3‐HB–Gpr109a signaling promotes extracellular calcium (Ca2+) influx. The elevation of intracellular Ca2+ level reduces the release of Ca2+ from the endothelium reticulum (ER) to mitochondria, thus inhibits ER stress triggered by ER Ca2+ store depletion. As NLRP3 inflammasome can be activated by ER stress, 3‐HB can inhibit the activation of NLRP3 inflammasome, which triggers the increase of M1 macrophage proportion and the inhibition of cholesterol efflux. It is concluded that daily nutritional supplementation of 3‐HB attenuates atherosclerosis in mice.

Atherosclerosis is a chronic inflammatory disease that can cause acute cardiovascular events. Activation of the NOD‐like receptor family, pyrin domain containing protein 3 (NLRP3) inflammasome enhances atherogenesis, which links lipid metabolism to sterile inflammation. This study examines the impact of an endogenous metabolite, namely ketone body 3‐hydroxybutyrate (3‐HB), on a mouse model of atherosclerosis. It is found that daily oral administration of 3‐HB can significantly ameliorate atherosclerosis. Mechanistically, 3‐HB is found to reduce the M1 macrophage proportion and promote cholesterol efflux by acting on macrophages through its receptor G‐protein‐coupled receptor 109a (Gpr109a). 3‐HB–Gpr109a signaling promotes extracellular calcium (Ca2+) influx. The elevation of intracellular Ca2+ level reduces the release of Ca2+ from the endothelium reticulum (ER) to mitochondria, thus inhibits ER stress triggered by ER Ca2+ store depletion. As NLRP3 inflammasome can be activated by ER stress, 3‐HB can inhibit the activation of NLRP3 inflammasome, which triggers the increase of M1 macrophage proportion and the inhibition of cholesterol efflux. It is concluded that daily nutritional supplementation of 3‐HB attenuates atherosclerosis in mice. [ABSTRACT FROM AUTHOR]

Abstract: Sodium salts of d-3-hydroxybutyrate (D-3-HB), dl-3-hydroxybutyrate (DL-3-HB) and methyl (d)-3-hydroxybutyrate (M-3-HB), are derivatives of 3-hydroxybutyric acid (3-HB), a ketone body that is produced in vivo in animals including human. D-3-HB is the most common degradation product of microbial polyhydroxyalkanoates (PHA) that have been investigated for tissue engineering application. This study evaluated the in vitro effect of PHA degradation product 3-HB and its derivatives (collectively called 3-HB derivatives) on cell apoptosis and cytosolic Ca2+ concentration of mouse glial cells. Results showed that the percentage of cells undergoing apoptosis decreased significantly in the presence of 3-HB and its derivatives as evidenced by flow cytometry. The in vitro study on cytosolic Ca2+ concentration demonstrated that 3-HB derivatives dramatically elevated the cytosolic Ca2+ concentration. Both the extracellular and intracellular Ca2+ contributed as the sources of such Ca2+ concentration elevation. The effect of 3-HB derivatives on cytosolic Ca2+ concentration could be reduced by nitredipine, an l-type voltage-dependent calcium channel antagonist. In comparison, M-3-HB worked more efficiently than D-3-HB and DL-3-HB did as M-3-HB is more efficient in permeation into the cells. All results indicated that 3-HB derivatives had an inhibitory effect on cell apoptosis which is mediated by signaling pathways related to the elevation of cytosolic Ca2+ concentration. This positive effect helps explain the biocompatibility observed for PHA, it also points to the possibility of 3-HB derivatives regardless of chirality to become an effective neural protective agent. [Copyright &y& Elsevier]

Green tea has been purported to have beneficial health effects including protective effects against oxidative stress. Acetaminophen (APAP) is a widely used analgesic drug that can cause acute liver injury in overdose situations. These studies explored the effects of green tea extract (GTE) on APAP-induced hepatotoxicity in liver tissue extracts using ultra performance liquid chromatography/quadrupole time-of-flight mass spectrometry and nuclear magnetic resonance spectroscopy. Mice were orally administered GTE, APAP or GTE and APAP under three scenarios. APAP alone caused a high degree of hepatocyte necrosis associated with increases in serum transaminases and alterations in multiple metabolic pathways. The time of GTE oral administration relative to APAP either protected against or potentiated the APAP-induced hepatotoxicity. Dose dependent decreases in histopathology scores and serum transaminases were noted when GTE was administered prior to APAP; whereas, the opposite occurred when GTE was administered after APAP. Similarly, metabolites altered by APAP alone were less changed when GTE was given prior to APAP. Significantly altered pathways included fatty acid metabolism, glycerophospholipid metabolism, glutathione metabolism, and energy pathways. These studies demonstrate the complex interaction between GTE and APAP and the need to employ novel analytical strategies to understand the effects of dietary supplements on pharmaceutical compounds., (Published by Elsevier Ltd.)