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

• Published in: Biomedicine & pharmacotherapy Vol. 164; p. 114956
• Main Authors: Gan, Changpei, Wang, Jing, Wang, Yaogeng, Martínez-Chávez, Alejandra, Hillebrand, Michel, de Vries, Niels, Beukers, Joke, Lebre, Maria C., Wagenaar, Els, Rosing, Hilde, Klarenbeek, Sjoerd, Bleijerveld, Onno B., Song, Ji-Ying, Altelaar, Maarten, Beijnen, Jos H., Schinkel, Alfred H.
• Format: Journal Article
• Language: English
• Published: France Elsevier Masson SAS 01-08-2023; Elsevier
• Subjects: Acute phase response; Animals; Capecitabine; Carboxylic Ester Hydrolases - genetics; Carboxylic Ester Hydrolases - metabolism; Ces1 enzymes; Female; Inflammation; Irinotecan; Lipids; Male; Mammals; Metabolic Syndrome; Mice; Obesity; Obesity - metabolism; Prodrugs; Irinotecan; Obesity; Inflammation; Ces1 enzymes; Capecitabine; Acute phase response
• ISSN: 0753-3322; 1950-6007
• DOI: 10.1016/j.biopha.2023.114956

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.
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•Spontaneous carboxylesterase Ces1c/d/e deletion mutant shows altered pharmacokinetics.•Carboxylesterases Ces1c/d/e hydrolyze irinotecan and capecitabine in vivo.•Ces1c/d/e deletion alters lipid homeostasis and exacerbates adipocyte inflammation.•Ces1c/d/e deletion exacerbates high-fat diet induced obesity and diabetes.•Ces1c/d/e deficiency causes fatty liver and activates hepatic acute-phase response.