Pharmacological Downregulation of Fetuin-A Attenuates TLR4-mediated Neuroinflammation in Aged Rats with Minimal Hepatic Encephalopathy

Abstract Minimal hepatic encephalopathy (MHE) is a neurological complication associated with chronic liver disease characterized by subtle cognitive impairment and neuroinflammation, particularly in the aging population. However, the molecular mechanisms underlying age-associated MHE remain poorly understood. The present study investigated the role of Fetuin-A-mediated neuroinflammation and its potential as a therapeutic target in the management of MHE in old rats using pioglitazone in a thioacetamide (TAA)-induced MHE model in aged rats. Old male rats were administered TAA (50 mg/kg) for 14 days to induce MHE, followed by pioglitazone treatment (3 mg/kg) for 7 days. Western blot and immunofluorescence analyses revealed elevated hippocampal Fetuin-A expression in MHE rats, accompanied by activation of the TLR4/MyD88/NF-κB signaling pathway and increased inflammatory cytokines (IL-6 and TNF-α). Pioglitazone treatment significantly reduced Fetuin-A expression, suppressed TLR4-mediated neuroinflammatory signaling, and decreased astrocyte activation. Furthermore, histological and Golgi-Cox analyses demonstrated restoration of neuronal density, dendritic arborization, and spine density in the hippocampus of old MHE rats after Fetuin-A suppression. Behavioral analyses further confirmed the molecular and histological findings. Thus, increased Fetuin-A acts as a proinflammatory molecule in the old MHE hippocampus, mediating neuroinflammation, and its attenuation alleviates the same.