Ectopic expression of alpha 1,6 fucosyltransferase in mice causes steatosis in the liver and kidney accompanied by a modification of lysosomal acid lipase

The alpha1,6 fucosyltransferase (alpha1,6 FucT) catalyzes the transfer of a fucose from GDP-fucose to the innermost GlcNAc residue of N-linked glycans via an alpha1,6 linkage. alpha1,6 FucT was overexpressed in transgenic mic e under the control of a combined cytomegalovirus and chicken beta -actin p romoter. Histologically numerous small vacuoles, in which lipid droplets ha d accumulated, were observed in hepatocytes and proximal renal tubular cell s. Electron microscopic studies showed that the lipid droplets were membran e-bound and apparently localized within the lysosomes. Cholesterol esters a nd triglycerides were significantly increased in liver and kidney of the tr ansgenic mice. Liver lysosomal acid lipase (LAL) activity was significantly lower in the transgenic mice compared to the wild mice, whereas LAL protei n level, which was detected immunochemically, was increased, indicating tha t the specific activity of LAL was much lower in the transgenic mice. In al l of the transgenic and nontransgenic mice examined, the activity of liver LAL was negatively correlated with the level of alpha1,6 FucT activity. As evidenced by lectin and immunoblot analysis, LAL was found to be more fucos ylated in the transgenic mice, suggesting that the aberrant fucosylation of LAL causes an accumulation of inactive LAL in the lysosomes. Such an accum ulation of inactive LAL could be a likely cause for a steatosis in the lyso somes of the liver and kidney in the case of the alpha1,6 FucT transgenic m ice.