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 4

SerBut suppresses plasma LDL-C and reduces liver damage markers.

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SerBut suppresses plasma LDL-C and reduces liver damage markers. Plasma ...
Plasma taken at 6 weeks of treatment in the regimen described in Figure 3A. (A–D) Blood chemical analysis pooled between 2 duplicate studies: (A) Percentage LDL/total cholesterol, (B) percentage HDL/total cholesterol, (C) total cholesterol, and (D) triglycerides. (E–G) Blood chemical analysis: (E) alanine transaminase (ALT), (F) aspartate aminotransferase (AST), and (G) lipase. P values less than 0.10 are shown. (H) Average weight of mice in water- and SerBut-treated groups. “B6,NC” denotes 3 age-matched C57BL/6 mice on a normal diet as a non-statistical comparison to visualize healthy examples. Data points represent individual mice displayed with median ± SEM. Data in A–D represent 2 independent pooled experiments: n = 10 per group per experiment for water- and SerBut-treated groups; n = 10 in a single experiment for NaBut-treated group. 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.