Regulation of rat hepatocyte protein kinase C beta isoenzymes by the lipid peroxidation 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-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 betaI and, to a much greater extent, PKC betaII activities were markedly increased by 0.1 micromol/L HNE (final concentration in cell medium) whereas they were unaffected or even inhibited by 1 to 10 micromol/L HNE. On the contrary, the calcium independent PKC delta activity was inhibited by 0.1 micromol/L and increased by 1 and 10 micromol/L. Further, we show here that HNE-induced stimulation of PKC betaI and betaII 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 micromol/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.
Chiarpotto
E
E
Department of Clinical and Biological Sciences, University of Torino, S. Luigi Gonzaga Hospital, Torino, Italy.
Domenicotti
C
C
Paola
D
D
Vitali
A
A
Nitti
M
M
Pronzato
M A
MA
Biasi
F
F
Cottalasso
D
D
Marinari
U M
UM
Dragonetti
A
A
Cesaro
P
P
Isidoro
C
C
Poli
G
G
D000447:Aldehydes / Q000378:metabolism* / Q000494:pharmacology; D000818:Animals; D001692:Biological Transport / Q000187:drug effects; D002402:Cathepsin D / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D005978:Glutathione / Q000378:metabolism; D006023:Glycoproteins / Q000378:metabolism; D007527:Isoenzymes / Q000378:metabolism*; D008054:Lipid Peroxides / Q000378:metabolism*; D008099:Liver / Q000166:cytology / Q000187:drug effects / Q000201:enzymology*; D008247:Lysosomes / Q000378:metabolism; D008297:Male; D010770:Phosphotransferases / Q000187:drug effects; D011233:Precipitin Tests; D011493:Protein Kinase C / Q000378:metabolism*; D064546:Protein Kinase C beta; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction / Q000502:physiology
D000447:Aldehydes; D006023:Glycoproteins; D007527:Isoenzymes; D008054:Lipid Peroxides; D010770:Phosphotransferases; D011493:Protein Kinase C; D064546:Protein Kinase C beta; D002402:Cathepsin D; D005978:Glutathione; C027576:4-hydroxy-2-nonenal