Role of Metabolic Nuclear Receptors in Acute Liver Injury and Drug-Induced Hepatotoxicity

Metabolic nuclear receptors (NRs) are ligand-activated transcription factors central to metabolic homeostasis and detoxification. While their roles in chronic liver diseases have been extensively reviewed, comprehensive review of metabolic NRs in acute liver injury (ALI) is scarce. This review summarizes the current knowledge on how metabolic NRs modulate ALI, with particular focus on those frequently-studied NRs including farnesoid X receptor, peroxisome proliferator-activated receptors and pregnane X receptor, as well as on the less-characterized liver X receptor and constitutive androstane receptor. Current evidence indicates that activation of farnesoid X receptor, peroxisome proliferator-activated receptor α, liver X receptor is hepatoprotective against ALI, while activation of proliferator-activated receptor γ, pregnane X receptor or constitutive androstane receptor plays a major role in potentiating acetaminophen hepatotoxicity and ALI, albeit conclusions from some studies could be context-dependent and controversial. The current review summarizes the roles and mechanisms for how metabolic NRs regulate ALI, which would help guide the future research on metabolic NRs for treating ALI.