Natural deletion of mouse carboxylesterases Ces1c/d/e impacts drug metabolism and metabolic syndrome development

Changpei Gan, Jing Wang, Yaogeng Wang, Alejandra Martínez-Chávez, Michel Hillebrand, Niels de Vries, Joke Beukers, Maria C. Lebre, Els Wagenaar, Hilde Rosing, Sjoerd Klarenbeek, Onno B. Bleijerveld, Ji Ying Song, Maarten Altelaar, Jos H. Beijnen, Alfred H. Schinkel*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

Mammalian carboxylesterase 1 enzymes can hydrolyze many xenobiotic chemicals and endogenous lipids. We here identified and characterized a mouse strain (FVB/NKI) in which three of the eight Ces1 genes were spontaneously deleted, removing Ces1c and Ces1e partly, and Ces1d entirely. We studied the impact of this Ces1c/d/e deficiency on drug and lipid metabolism and homeostasis. Ces1c/d/e-/- mice showed strongly impaired conversion of the anticancer prodrug irinotecan to its active metabolite SN-38 in plasma, spleen and lung. Plasma hydrolysis of the oral anticancer prodrug capecitabine to 5-DFCR was also profoundly reduced in Ces1c/d/e-/- mice. Our findings resolved previously unexplained FVB/NKI pharmacokinetic anomalies. On a medium-fat diet, Ces1c/d/e-/- female mice exhibited moderately higher body weight, mild inflammation in gonadal white adipose tissue (gWAT), and increased lipid load in brown adipose tissue (BAT). Ces1c/d/e-/- males showed more pronounced inflammation in gWAT and an increased lipid load in BAT. On a 5-week high-fat diet exposure, Ces1c/d/e deficiency predisposed to developing obesity, enlarged and fatty liver, glucose intolerance and insulin resistance, with severe inflammation in gWAT and increased lipid load in BAT. Hepatic proteomics analysis revealed that the acute phase response, involved in the dynamic cycle of immunometabolism, was activated in these Ces1c/d/e-/- mice. This may contribute to the obesity-related chronic inflammation and adverse metabolic disease in this strain. While Ces1c/d/e deficiency clearly exacerbated metabolic syndrome development, long-term (18-week) high-fat diet exposure overwhelmed many, albeit not all, observed phenotypic differences.

Original languageEnglish
Article number114956
JournalBiomedicine and Pharmacotherapy
Volume164
DOIs
Publication statusPublished - Aug 2023

Bibliographical note

Funding Information:
This work was funded in part by the China Scholarship Council (CSC Scholarship No. 201506240145 to CPG). OBB and MA are supported by the Dutch NWO X-omics Initiative .

Publisher Copyright:
© 2023 The Authors

Funding

This work was funded in part by the China Scholarship Council (CSC Scholarship No. 201506240145 to CPG). OBB and MA are supported by the Dutch NWO X-omics Initiative .

Keywords

  • Acute phase response
  • Capecitabine
  • Ces1 enzymes
  • Inflammation
  • Irinotecan
  • Obesity

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