Carboxylesterase 1 family knockout alters drug disposition and lipid metabolism

Gan, Changpei; Wang, Jing; Martínez-Chávez, Alejandra; Hillebrand, M. J. X.; Vries, Niels de; Beukers, Joke; Wagenaar, Els; Wang, Yaogeng; Lebre, Maria C.; Rosing, Hilde; Klarenbeek, Sjoerd; Ali, Rahmen Bin; Pritchard, Colin E.J.; Huijbers, Ivo J.; Beijnen, Jos H.; Schinkel, Alfred H.

doi:10.1016/j.apsb.2022.10.017

Cited by 13 publications

(3 citation statements)

References 35 publications

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“…3g, Supplementary Table 1, sheet 3). Highly DEGs in the SPF DOWN cluster (black labels) include genes that have been associated with tumor suppression and CRC 39–41 ( Meg3 , Cwh43, Naprt) , lipid metabolism and detoxification 42 ( Ces1f ), and bactericidal/antimicrobial activity 43 ( Iapp ) (Extended Data Fig. 4e).…”

Section: Resultsmentioning

confidence: 99%

ATF6 activation alters colonic lipid metabolism causing tumor-associated microbial adaptation

Coleman,

Sorbie,

Bierwith

et al. 2023

Preprint

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The induction of endoplasmic reticulum unfolded protein responses (UPRER) contributes to cancer development and progression. We recently linked microbiota-related triggers to the tumor-promoting role of signal transducer activating transcription factor 6 (ATF6) in the colon. Here we substantiate the clinical relevance of ATF6 and related bacterial genera in colorectal cancer patient cohorts. Spatial and longitudinal bacterial profiling in ATF6 transgenic mice (nATF6IEC) identified tumor-initiating and tumor-progressing shifts in the mucosa-associated microbiota. Transcriptional analysis in intestinal epithelial cells (IEC) of germ-free and specific pathogen-free nATF6IECmice defined bacteria-specific changes in cellular metabolism enriched for fatty acid biosynthesis. Untargeted metabolomics, isotope-labeling in intestinal organoids and FASN inhibition confirmed ATF6-mediated involvement of long-chain fatty acids in tumorigenesis. Multi-omics data integration identified a bacteria-lipid network characterized by fatty acid efflux, catabolism and detoxification. We postulate chronic ATF6 signaling to drive a clinically relevant pathologic response altering lipid metabolism to select for a tumor-promoting microbiota.Graphical AbstractChronic ATF6 signaling in the colonic epithelium alters lipid metabolism to select a tumor-promoting microbiotanATF6 expression is induced in intestinal epithelial cells in transgenic mice (nATF6IEC)Biallelic nATF6IECgerm-free mice (grey circle) and floxed or monoallelic specific pathogen-free mice (black circle) remain in a state of homeostasis (yellow circle), while biallelic specific pathogen-free mice (black circle) develop spontaneous colon tumorigenesis (red circle)Mechanistically, biallelic nATF6IECmice in the presence of an intestinal microbiota alter colonic lipid metabolism, including the upregulation of FasnThe microbial lipid-response to the altered lipid milieu results in dysbiosis and the subsequent formation of colon adenomasInhibition of FASN in biallelic nATF6IECmice prevents colon tumor formation (yellow arrow)Created withBioRender.comnATF6: activated activating transcription factor 6; LCFA: long-chain fatty acids; SAFA: saturated fatty acids; Fasn: fatty acid synthase; C75 i.p.: intraperitoneal injection of the Fasn inhibitor C75.

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Section: Resultsmentioning

confidence: 99%

ATF6 activation alters colonic lipid metabolism causing tumor-associated microbial adaptation

Coleman,

Sorbie,

Bierwith

et al. 2023

Preprint

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“…31 To rigorously test the involvement of Ces1c in cabazitaxel plasma retention in mice, we used recently established Ces1 cluster knockout and spontaneous Ces1cde mutant strains. 32,33…”

Section: Introductionmentioning

confidence: 99%

“…In contrast, mouse Ces1c, one of the 8 mouse Ces1 proteins, is secreted from the liver into plasma . To rigorously test the involvement of Ces1c in cabazitaxel plasma retention in mice, we used recently established Ces1 cluster knockout and spontaneous Ces1cde mutant strains. , …”

Section: Introductionmentioning

confidence: 99%

Interplay of Ritonavir-Boosted Oral Cabazitaxel with the Organic Anion-Transporting Polypeptide (OATP) Uptake Transporters and Carboxylesterase 1 in Mice

Loos,

Ferreira Martins,

Rijmers

et al. 2024

Mol. Pharmaceutics

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Intravenously administered chemotherapeutic cabazitaxel is used for palliative treatment of prostate cancer. An oral formulation would be more patient-friendly and reduce the need for hospitalization. We therefore study determinants of the oral pharmacokinetics of cabazitaxel in a ritonavir-boosted setting, which reduces the CYP3A-mediated first-pass metabolism of cabazitaxel. We here assessed the role of organic anion-transporting polypeptides (OATPs) in the disposition of orally boosted cabazitaxel and its active metabolites, using the Oatp1a/b-knockout and the OATP1B1/1B3-transgenic mice. These transporters may substantially affect plasma clearance and hepatic and intestinal drug disposition. The pharmacokinetics of cabazitaxel and DM2 were not significantly affected by Oatp1a/b and OATP1B1/1B3 activity. In contrast, the plasma AUC0–120 min of DM1 in Oatp1a/b –/– was 1.9-fold (p < 0.05) higher than that in wild-type mice, and that of docetaxel was 2.4-fold (p < 0.05) higher. We further observed impaired hepatic uptake and intestinal disposition for DM1 and docetaxel in the Oatp-ablated strains. None of these parameters showed rescue by the OATP1B1 or -1B3 transporters in the humanized mouse strains, suggesting a minimal role of OATP1B1/1B3. Ritonavir itself was also a potent substrate for mOatp1a/b, showing a 2.9-fold (p < 0.0001) increased plasma AUC0–120 min and 3.5-fold (p < 0.0001) decreased liver-to-plasma ratio in Oatp1a/b –/– compared to those in wild-type mice. Furthermore, we observed the tight binding of cabazitaxel and its active metabolites, including docetaxel, to plasma carboxylesterase (Ces1c) in mice, which may complicate the interpretation of pharmacokinetic and pharmacodynamic mouse studies. Collectively, these results will help to further optimize (pre)clinical research into the safety and efficacy of orally applied cabazitaxel.

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