Acetaldehyde induces c-fos and c-jun proto-oncogenes in fat-storing cell cultures through protein kinase C activation.
Hepatic fibrosis is an important morphological feature of alcohol-induced liver injury. We previously reported that acetaldehyde stimulates collagen I and fibronectin gene transcription in rat fat-storing cell (FSC) culture. We here evaluated whether acetaldehyde increases Col I and FN gene transcription through the induction of c-fos and c-jun proto-oncogenes and studied the possible role played by protein kinase C (PKC) and c-AMP. FSCs, isolated from rat liver on a Nycodenz density gradient, were exposed to acetaldehyde for 1/2, 1, 3, 6, 12, 24 hr and for 10, 20, 30, 45, 60, 90 min in the experiments for jun and fos expression, respectively. Acetaldehyde produced a rapid and transient induction of fos mRNA (undetectable at t = 0, peak at t = 45 and still evident at t = 90). Jun mRNA was weakly expressed in unstimulated FSCs; acetaldehyde induced a prolonged activation of jun expression up to 24 hr with a peak at 3 hr. To study the role of PKC were repeated the experiments in the presence of Staurosporine and H-7. These inhibitors of PKC activity blocked the stimulatory effect of acetaldehyde on fos and jun mRNA expression. Furthermore, they abolished the stimulatory effect of acetaldehyde on collagen I and fibronectin gene expression by FSCs. Acetaldehyde increased the cell membrane PKC activity in FSC cultures in a dose-dependent way. Intracellular cAMP levels were not significantly modified by acetaldehyde in the first 30 min of incubation. We conclude that acetaldehyde increases procollagen I and fibronectin gene transcription in FSCs, possibly through c-fos and c-jun expression, and that PKC may play a regulatory role in this chain of events.
Casini
A
A
Dipartimento di Fisiopatologia Clinica, Università di Firenze, Italy.
Galli
G
G
Salzano
R
R
Ceni
E
E
Franceschelli
F
F
Rotella
C M
CM
Surrenti
C
C
D000079:Acetaldehyde / Q000494:pharmacology*; D000818:Animals; D015152:Blotting, Northern; D002478:Cells, Cultured; D003094:Collagen / Q000235:genetics; D000242:Cyclic AMP / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation / Q000187:drug effects; D005260:Female; D005353:Fibronectins / Q000235:genetics; D005786:Gene Expression Regulation / Q000187:drug effects; D011493:Protein Kinase C / Q000378:metabolism*; D016760:Proto-Oncogene Proteins c-fos / Q000235:genetics*; D016755:Proto-Oncogene Proteins c-jun / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D014158:Transcription, Genetic / Q000187:drug effects
D005353:Fibronectins; D016760:Proto-Oncogene Proteins c-fos; D016755:Proto-Oncogene Proteins c-jun; D012333:RNA, Messenger; D003094:Collagen; D000242:Cyclic AMP; D011493:Protein Kinase C; D000079:Acetaldehyde