Downregulation of Glt25d1 aggravates carbon tetrachloride-induced acute hepatic injury through activation of the TGF-β1/Smad2 signaling pathway

Collagen β (1-O) galactosyltransferase 1 (GLT25D1) has been reported to transfer galactose to hydroxylysine residues via β (1-O) linkages in collagen. The present study investigated the function of the collagen galactosyltransferase activity of GLT25D1 against carbon tetrachloride (CCl(4))-induced acute liver injury in vitro. Glt25d1(+/−) mice and wild-type (WT) mice were injected intraperitoneally with the same dose of CCl(4). The grade of hepatic injury and the extent of hepatocyte necrosis in the acute phase were assessed 48 h following CCl(4) injection. Hepatocyte necrosis was evaluated by histological examination and by serum alanine aminotransferase and aspartate aminotransferase levels, which were higher in the Glt25d1(+/−) mice compared with those in the WT mice. Reverse transcription-quantitative polymerase chain reaction was performed, and the results demonstrated that the mRNA expression levels of inflammatory cytokines, including tumor necrosis factor-α and interleukin-6 were significantly increased in the Glt25d1(+/−) mice. Furthermore, western blot analyses were performed, and the results demonstrated that the protein levels of cleaved caspase-3 and −9 were also markedly increased in the Glt25d1(+/−) liver, indicating that hepatocyte apoptosis was induced. Additionally, the expression levels of transforming growth factor (TGF)-β1 and phosphorylated small mothers against decapentaplegic (Smad)2 were markedly upregulated, indicating activation of the TGF-β1/Smad2 signaling pathway during CCl(4)-induced acute liver injury in Glt25d1(+/−) mice. CCl(4) administration also resulted in severe damage to Glt25d1(+/−) primary hepatocytes in vitro. Taken together, the downregulation of Glt25d1 deteriorated CCl(4)-induced liver injury in mice, which may involve triggering inflammatory responses, apoptosis and TGF-β1/Smad2 signaling pathway activation.