Regulation of rat hepatocyte protein kinase C beta isoenzymes by the lipidperoxidation product 4-hydroxy-2,3-nonenal: A signaling pathway to modulate vesicular transport of glycoproteins

A major aldehydic end product of the peroxidation of arachidonic acid, 4-hy droxy-2,3-nonenal (HNE), has recently been considered for its potential inv olvement in a variety of cell functions. Here we report on the differential regulation of rat hepatocyte protein kinase C (PKC) isoforms by concentrat ions of HNE actually detectable in specific biological fluids or tissues. P KC beta I and, to a much greater extent, PKC beta II activities were marked ly increased by 0.1 mu mol/L HNE (final concentration in cell medium) where as they were unaffected or even inhibited by 1 to 10 mu mol/L HNE. On the c ontrary, the calcium independent PKC delta activity was inhibited by 0.1 mu mol/L and increased by 1 and 10 mu mol/L. Further, we show here that HNE-i nduced stimulation of PKC beta I and beta II activities, both in cytosolic and in membrane fractions, is paralleled by a marked stimulation of the ant erograde transport of a lysosomal enzyme within the central vacuolar system . In fact, the treatment with 0.1 mu mol/L HNE accelerated the PKC-dependen t transport of lysosomal procathepsin D from the trans-Golgi network to the endosomal-lysosomal compartment and, in addition, increased the exocytosis of mature cathepsin D (CD) from these compartments. On the other hand, hep atocyte cotreatment with a selective inhibitor of classic PKCs prevented th e aldehyde-induced activation of CD transport. These results support the po ssible involvement of HNE in the PKC-dependent regulation of the traffic of secretory glycoproteins, and point to remarkable implications of this alde hyde in the pathophysiology of various exocytic processes including hepatoc yte lipoprotein secretion.