Evaluating plasma carboxylesterase 1 as a protein biomarker for pharmacokinetics and metabolic dysfunction-associated steatotic liver disease.

Carboxylesterase 1 (CES1) is the most abundant hepatic hydrolase responsible for metabolizing many clinically important medications. Hepatic CES1 also plays a role in regulating lipid homeostasis. This study aimed to determine whether plasma CES1 protein levels reflect hepatic CES1 abundance and serve as a biomarker of the pharmacokinetics of CES1-substrate drugs and of metabolic dysfunction-associated steatotic liver disease (MASLD). We quantified CES1 protein levels in matched human livers and plasma from adults with biopsy-confirmed MASLD (n = 17), in normal liver tissues (n = 6), and in plasma from healthy volunteers enrolled in an enalapril pharmacokinetic study (n = 19). First, we found no correlation between hepatic and plasma CES1 levels in matched liver and plasma samples from patients with MASLD. Second, plasma CES1 correlated with enalaprilat exposure, although the correlation did not reach statistical significance. Third, plasma CES1 concentrations were approximately 8-fold higher in patients with MASLD than in healthy subjects (median 141.9 vs 16.2 ng/mL), whereas hepatic CES1 levels were comparable between MASLD and normal liver tissues. Moreover, plasma CES1 concentrations rose stepwise across histologic NAFLD activity score (NAS) strata (healthy < NAS 1-4 < NAS ≥ 5). Fourth, the machine learning model, Lasso logistic regression, showed that the CES1-informed classifier consistently outperformed those based on clinical features in differentiating MASLD patients from healthy subjects and across disease severity (NAS 1-4 vs NAS ≥ 5). Together, these data position plasma CES1 as a potential biomarker for diagnosing MASLD and staging the disease. SIGNIFICANCE STATEMENT: The findings of this study indicate that plasma carboxylesterase 1 may act as a substrate-dependent biomarker for the pharmacokinetics of drugs metabolized by the enzyme. Additionally, this study highlights plasma carboxylesterase 1 as a potential noninvasive biomarker of metabolic dysfunction-associated steatotic liver disease/metabolic dysfunction-associated steatohepatitis that can complement existing diagnostic tools and provide a more comprehensive assessment of disease progression.