A prometabolite strategy inhibits cardiometabolic disease in an ApoE–/– murine model of atherosclerosis
Taryn N. Beckman, Lisa R. Volpatti, Salvador Norton de Matos, Anna J. Slezak, Joseph W. Reda, Ada Weinstock, Leah Ziolkowski, Alex Turk, Erica Budina, Shijie Cao, Gustavo Borjas, Jung Woo Kwon, Orlando deLeon, Kirsten C. Refvik, Abigail L. Lauterbach, Suzana Gomes, Eugene B. Chang, Jeffrey A. Hubbell
Taryn N. Beckman, Lisa R. Volpatti, Salvador Norton de Matos, Anna J. Slezak, Joseph W. Reda, Ada Weinstock, Leah Ziolkowski, Alex Turk, Erica Budina, Shijie Cao, Gustavo Borjas, Jung Woo Kwon, Orlando deLeon, Kirsten C. Refvik, Abigail L. Lauterbach, Suzana Gomes, Eugene B. Chang, Jeffrey A. Hubbell
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Research Article Inflammation Therapeutics

A prometabolite strategy inhibits cardiometabolic disease in an ApoE–/– murine model of atherosclerosis

Abstract

Butyrate, a microbiome-derived short-chain fatty acid with pleiotropic effects on inflammation and metabolism, has been shown to significantly reduce atherosclerotic lesions, rectify routine metabolic parameters such as low-density lipoprotein cholesterol (LDL-C), and reduce systemic inflammation in murine models of atherosclerosis. However, its foul odor, rapid metabolism in the gut and thus low systemic bioavailability limit its therapeutic effectiveness. Our laboratory has engineered an ester-linked L-serine conjugate to butyrate (SerBut) to mask its taste and odor and to coopt amino acid transporters in the gut to increase its systemic bioavailability, as determined by tissue measurements of free butyrate, produced by hydrolysis of SerBut. In an apolipoprotein E–knockout (ApoE)–/– mouse model of atherosclerosis, SerBut reduced systemic LDL-C, proinflammatory cytokines, and circulating neutrophils. SerBut enhanced inhibition of plaque progression and reduced monocyte accumulation in the aorta compared with sodium butyrate. SerBut suppressed liver injury biomarkers alanine transaminase and aspartate aminotransferase and suppressed steatosis in the liver. SerBut overcomes several barriers to the translation of butyrate and shows superior promise in slowing atherosclerosis and liver injury compared with equidosed sodium butyrate.

Authors

Taryn N. Beckman, Lisa R. Volpatti, Salvador Norton de Matos, Anna J. Slezak, Joseph W. Reda, Ada Weinstock, Leah Ziolkowski, Alex Turk, Erica Budina, Shijie Cao, Gustavo Borjas, Jung Woo Kwon, Orlando deLeon, Kirsten C. Refvik, Abigail L. Lauterbach, Suzana Gomes, Eugene B. Chang, Jeffrey A. Hubbell

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Figure 2

Seryl modification increases oral bioavailability of butyrate in atherosclerotic organs.

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Seryl modification increases oral bioavailability of butyrate in atheros...
(A) Experimental schema of ApoE–/– mice fed an HFD for 8 weeks, after which they received a single equimolar gavage of 272 mM butyrate as SerBut or NaBut. After 3 hours, mice were perfused, and the amount of butyrate per gram of tissue was measured in the (B) heart, (C) aorta, (D) liver, (E) inguinal lymph nodes (ILNs), (F) kidney, (G) spleen, (H) lung, (I) mesenteric lymph nodes (MLNs), and (J) plasma (μM). n = 8 mice in SerBut and NaBut groups. n = 6 mice in PBS group. (K) Experimental schema of C57BL/6 mice fed a normal chow (NC) diet, after which they received a single equimolar gavage of 272 mM butyrate as SerBut or NaBut. (L) Diagram of gut dissection. (M) Upper small intestine. (N) Lower small intestine. (O) Ileum. (P) Colon. Quantification was performed by LC-MS/MS upon derivatization with 3-nitrophenylhydrazine. Free butyrate (g) was normalized to tissue weight (g). Data points represent individual mice displayed with median ± SEM. Statistical analyses were performed using a 1-way ANOVA with Tukey’s, Welch’s (if SDs were significantly different by Bartlett and Brown-Forsyth tests), or Kruskal-Wallis (if data were not normally distributed determined by Shapiro-Wilk test) post hoc test. P values less than 0.10 are shown.