Regulation of Rat Hepatocyte Protein Kinase C β Isoenzymes by the Lipid Peroxidation Product 4–Hydroxy–2,3–Nonenal: A Signaling Pathway to Modulate Vesicular Transport of Glycoproteins

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Abstract
A major aldehydic end product of the peroxidation of arachidonic acid, 4–hydroxy–2,3–nonenal (HNE), has recently been considered for its potential involvement in a variety of cell functions. Here we report on the differential regulation of rat hepatocyte protein kinase C (PKC) isoforms by concentrations of HNE actually detectable in specific biological fluids or tissues. PKC βI and, to a much greater extent, PKC βII activities were markedly increased by 0.1 μmol/L HNE (final concentration in cell medium) whereas they were unaffected or even inhibited by 1 to 10 μmol/L HNE. On the contrary, the calcium independent PKC δ activity was inhibited by 0.1 μmol/L and increased by 1 and 10 μmol/L. Further, we show here that HNE–induced stimulation of PKC βI and βII activities, both in cytosolic and in membrane fractions, is paralleled by a marked stimulation of the anterograde transport of a lysosomal enzyme within the central vacuolar system. In fact, the treatment with 0.1 μmol/L HNE accelerated the PKC–dependent 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, hepatocyte cotreatment with a selective inhibitor of classic PKCs prevented the aldehyde–induced activation of CD transport. These results support the possible involvement of HNE in the PKC–dependent regulation of the traffic of secretory glycoproteins, and point to remarkable implications of this aldehyde in the pathophysiology of various exocytic processes including hepatocyte lipoprotein secretion.