Autotaxin as a potential biomarker in hepatic encephalopathy: Insights from a mouse model and cirrhotic patients.

Abstract

Hepatic encephalopathy (HE) is a debilitating neuropsychiatric condition associated with acute liver failure or advanced liver diseases, significantly affecting patient morbidity and mortality. Autotaxin (ATX), a lysophospholipase D that generates lysophosphatidic acid (LPA), has been proposed as a biomarker for liver fibrosis progression, but its role in HE remains poorly defined. This study aimed to explore the potential roles of ATX using in vivo TAA-induced HE models in mouse and clinical evaluations of cirrhotic patients with and without HE. ATX concentrations were quantified in plasma, liver tissue, and frontal cortex of HE mice, while ectonucleotide pyrophosphatase/phosphodiesterase 2 (Enpp2) gene expression and LPA levels were assessed in murine salivary glands. In parallel, serum and salivary ATX were measured in 7 cirrhotic patients with HE and 12 cirrhotic patients without HE. ATX concentrations were significantly elevated in the liver parenchyma and frontal cortex of TAA-induced HE mice compared to controls, whereas plasma ATX showed no significant difference. Enpp2 expression was upregulated 2.49-fold in salivary glands of HE mice, although salivary LPA concentrations did not differ between groups. Clinically, both serum and salivary ATX levels were significantly higher in cirrhotic patients with HE than in those without HE. Moreover, salivary ATX levels positively correlated with serum alkaline phosphatase (ALP) levels in the HE patient group. These findings demonstrate that ATX is elevated in key tissues and biofluids in both experimental and clinical HE, supporting its potential as a novel biomarker. Moreover, the data suggest that the ATX-LPA axis may contribute to HE pathophysiology, providing a foundation for future mechanistic studies and the exploration of targeted therapeutic strategies.