Systemic TGF-β1 reduction contributes to neuronal GLUT4 trafficking impairment in acute hepatic encephalopathy

Acute liver failure disrupts cerebral glucose homeostasis and contributes to neurological manifestations of hepatic encephalopathy (HE). Neurons, which partly rely on the insulin-sensitive glucose transporter GLUT4, may be particularly vulnerable to systemic metabolic disturbances. Transforming growth factor beta 1 (TGF-β1), implicated in HE pathogenesis, is known to modulate insulin signaling in peripheral tissues; however, its role in neuronal glucose handling remains poorly defined. In this study, we investigated whether reduction of peripheral TGF-β1 in HE impairs the neuronal GLUT4 status and whether this effect can be reproduced by systemic TGF-β1 neutralization (sTGF-β1n) in healthy mice. Both HE and sTGF-β1n increased GLUT4 immunoreactivity in MAP2-positive neurons and promoted its accumulation within the neuronal cytoplasm. Together with unaltered GLUT4 membrane levels, this suggests defective cytosol-to-membrane translocation or mobilization of the transporter. These changes were accompanied by altered PI3K/Akt/PKCζ signaling in HE only, but decreased AMPK phosphorylation in both model treatments, indicating the latter route to be the common mediator of impaired regulation of GLUT4 trafficking. While hypoglycemia and hyperinsulinemia were observed only in the HE model, selective sTGF-β1n reproduces alterations in neuronal GLUT4 distribution in the absence of hypoglycemia and hyperinsulinemia accompanying HE in the present model, indicating that TGF-β1 deficiency per se may contribute to this deficit. Our findings highlight TGF-β1 availability as a previously underappreciated modulator of neuronal glucose metabolism, and peripheral reduction of TGF-β1 as a factor potentially aggravating energy deficit in HE.