Speaker
Description
Background: Non-alcoholic fatty liver disease (NAFLD) is characterized by excessive triglyceride (TG) accumulation in hepatocytes, leading to progressive liver injury. Carboxylesterases CES1 and CES2 are critical hepatic lipolytic enzymes, yet their expression and activity are suppressed in obesity. Therapeutic strategies to restore CES1/2 function remain limited.
Methods: High-fat diet (HFD)-fed wild-type (WT) and liver X receptor alpha (LXRα) knockout (LXRα-/-) mice, along with lipid-loaded HepG2 cells, were treated with ORI, a natural diterpenoid and LXRα agonist. Hepatic lipid content, gene/protein expression, enzymatic activity assays, histological analyses, and pharmacokinetic assessments of CES-metabolized prodrugs (oseltamivir/irinotecan) were performed. Transcriptional regulation was evaluated via luciferase reporter assays, chromatin immunoprecipitation (ChIP), and siRNA-mediated knockdown of LXRα, CES1, or CES2.
Results: ORI treatment alleviated hepatic steatosis and reduced TG ac-cumulation by enhancing CES1 and CES2 transcription and enzymatic activity. LXRα deficiency impaired CES1/2 expression and function, ex-acerbated TG deposition, and altered the pharmacokinetics of CES-dependent prodrugs. Mechanistically, LXRα directly bound to LXREs within CES1 and CES2 promoters to activate transcription. The lipid-lowering effect of ORI was abolished in LXRα-/- mice and CES1/CES2-knockdown cells, indicating that its pharmacological activity depends on the LXRα-CES1/CES2 axis
Conclusions: Our study identifies the LXRα-CES1/CES2 axis as a key regulator of hepatic lipid metabolism. ORI restores CES1/2 expression and activity via LXRα activation, highlighting its potential as a therapeutic candidate for NAFLD.