Isoform-Specific Regulation of Mouse Carboxylesterase Expression and Activity by Prototypical Transcriptional Activators

Abstract

Nuclear receptors and transcription factors regulate the mRNA expression of many drug metabolizing enzymes, including the carboxylesterases (Ces). However, there are few data regarding whether these changes in mRNA expression result in alteration of protein levels or activity. In the present study, we sought to determine the isoform-specific regulation of hepatic Ces mRNA expression and activity following administration of pharmacological activators of the constitutive androstane receptor (CAR), pregnane X receptor (PXR) and nuclear factor-E2-related protein (Nrf2) to mice. The CAR activator 1,4-bis-[2-(3,5-dichloropyridyloxy)] benzene (TCPOBOP) and PXR ligand pregnenolone-16a-carbonitrile (PCN) increased Ces mRNA expression of various Ces2 isoforms, whereas the Nrf2 activator butylated hydroxyanisole (BHA) primarily reduced Ces3a mRNA expression and induced Ces1g mRNA. TCPOBOP and PCN increased Ces2 hydrolytic activity in an isoform-specific manner. Taken together, these data demonstrate that activation of CAR, PXR and Nrf2 regulates not only Ces mRNA expression, but also isoform-specific activity.

Combined Use of Bicyclol and Berberine Alleviates Mouse Nonalcoholic Fatty Liver Disease

“…As the promoting roles for lipolysis by CES2 has been well illustrated ( Li et al, 2016 ; Chalhoub et al, 2021 ), we thus speculate that bicyclol could also enhance the lipolysis process. Of note, PPARα and CES2 were downstream targets of p62-Nrf2 signaling ( Zhang et al, 2012 ; Baker et al, 2015 ; Tao et al, 2021 ). Our results further verified the protein expressions of p62 and Nrf2 were reduced significantly in WD- and WD/CCl 4 -induced model groups, while bicyclol but not berberine increased their expressions ( Figures 3A, B ).…”

“…Meanwhile, bicyclol also enhanced the PPARα-mediated β-oxidation, and this role was also verified by previous report ( Yu et al, 2009 ). Generally, CES2 was independent of the expression of PPARα ( Wen et al, 2019 ), while all of them could be regulated by the pleiotropic transcription factor Nrf2 ( Zhang et al, 2012 ; Baker et al, 2015 ; Tao et al, 2021 ). Nrf2 induced the downstream PPARα expression and was regulated by its upstream increased p62 to connect with Keap1 ( Zhang et al, 2012 ; Baker et al, 2015 ; Lee et al, 2020 ; Tao et al, 2021 ).…”

Hepatic carboxylesterases are differentially regulated in PPARα-null mice treated with perfluorooctanoic acid

“…Previous studies demonstrated that PFOA activates nuclear receptors including PPARα and CAR (Poole et al, 2001;Rosen et al, 2008) that may alter hepatic Ces expression/activity (Baker et al, 2015). As shown in Fig.…”

“…Ces enzyme activity in mouse hepatic microsomal fractions was determined by the hydrolysis of p-nitrophenyl valerate using a continuous spectrophotometric assay as described previously (Baker et al, 2015). Briefly, frozen livers (0.1-0.2 g) were homogenized in buffer (0.05 M Tris-HCl, 1.15% KCl, pH 7.4) and centrifugated at 9000 × g for 20 min at 4°C.…”

“…Two additional hepatic transcription factors, the pregnane X receptor (PXR) and constitutive androstane receptor (CAR), have also been shown to regulate the expression of Ces enzymes (Rosenfeld et al, 2003;Xu et al, 2009;Staudinger et al, 2010). Treatment of mice with either a CAR (1,4-bis-[2-(3,5-dichloro-pyridyloxy)]benzene, TCPOBOP) or PXR activator (pregnenolone-16α-carbonitrile) enhances the liver mRNA expression of Ces 1d, 2a, and 2c (CAR targets) and Ces 1c, 1d, 1g, 2a, 2c, and 2e (PXR targets), respectively (Baker et al, 2015). Likewise, hepatic Ces mRNA expression can be also altered by activators of the aryl hydrocarbon receptor (AhR) and the nuclear factor E2-related protein 2 (Nrf2) transcription factor (Zhang et al, 2012).…”