Loss of PPARα-UGT1 axis exacerbates triclosan-induced steatohepatitis in humanized UDP-glucuronosyltransferase 1 mice.

Triclosan (TCS) is an antimicrobial toxicant found in a wide range of consumer products and has been detected in human tissues at concentrations ranging from 0.001 to 5 ppm. Hepatotoxic chemicals such as TCS can cause steatotic liver disease, a condition referred to as toxicant-associated steatotic liver disease. Once TCS enters the body, it induces liver UDP-glucuronosyltransferase (UGT) 1A proteins, leading to the formation of TCS glucuronides, which are biologically inactive metabolites. The induction of UGT1A proteins by TCS is regulated by the nuclear receptor peroxisome proliferator-activated receptor α (PPARα). In this study, we evaluated the impact of TCS on the PPARα-UGT1 axis in steatohepatitis and hepatocellular carcinoma using humanized UGT1 (hUGT1) male mice. We have demonstrated that TCS exposure promotes liver tumorigenesis and induces human UGT1A1 and other human UGT1A proteins in the liver. Furthermore, our results demonstrate that UGT1A gene induction in the liver is dependent on PPARα. When PPARα-deficient hUGT1 mice (hUGT1/Pparα-/-) were exposed to TCS for 5 months, steatohepatitis was exacerbated, accompanied by increased fibrosis, immune cell infiltration, lipid accumulation, and hepatocyte ballooning. Finally, we assessed whether disruption of the PPARα-UGT1 axis contributes to liver tumorigenesis. Our data indicate that deletion of PPARα and consequent impairment of UGT1A gene induction in the liver have no effect on tumor progression and malignancy. Our hUGT1/Pparα-/- mouse model was a suitable model to study the TCS metabolism and how ablation of UGT1A proteins worsens TCS-induced metabolic dysfunction-associated steatohepatitis. SIGNIFICANCE STATEMENT: Triclosan strongly induces hepatic UGT1A gene expression through a PPARα-dependent mechanism in humanized UGT1 (hUGT1) mice. Loss of PPARα in hUGT1 mice augments triclosan-induced steatohepatitis, characterized by increased fibrosis, lipid accumulation, immune cell infiltration, and hepatocyte ballooning.