C/EBP-α ameliorates CCl(4)-induced liver fibrosis in mice through promoting apoptosis of hepatic stellate cells with little apoptotic effect on hepatocytes in vitro and in vivo.
CCAAT enhancer binding protein-α (C/EBP-α) is a transcript factor that regulates adipocyte differentiation and induces apoptosis in hepatic stellate cells (HSCs) in vivo and in vitro. However, the effect of C/EBP-α on hepatocytes in vivo remains unknown. This study investigated whether C/EBP-α exerts different apoptotic effects on hepatocytes and HSCs in vitro and in vivo. An adenovirus vector-expressing C/EBP-α gene was constructed, and a rat hepatic stellate cell lines (HSC-T6) and hepatocytes were transfected. A CCl(4)-induced liver fibrosis model in mice was also utilized. C/EBP-α induced apoptosis in hepatocytes and HSCs, but a significant difference between these cell types was observed in vitro. The mitochondrial pathway was involved in the apoptotic process and was predominant in HSC-T6 apoptosis. In the CCl(4)-induced mice liver fibrosis model, the administration of Ad-C/EBP-α decreased extracellular matrix deposition, including collagen and hydroxyproline content, and γ-GT levels, a marker of liver damage, were reduced significantly. Immunohistochemistry and TUNEL assay results showed an increase of apoptosis in HSCs, but hepatocytes were less affected. C/EBP-α induced differential apoptotic effects in hepatocytes and HSCs in vitro and in vivo. This differential effect could be a potential target for the treatment of hepatic fibrosis with little hepatic toxicity.
Department of Pathology, Shanghai Medical College, Fudan University, Shanghai, China.
Li-Li
LL
Tao
Yuan-Yuan
YY
Cheng
Di
D
Ding
Shuang
S
Mei
Jia-Wen
JW
Xu
Juan
J
Yu
Qi
Q
Ou-Yang
Long
L
Deng
Qi
Q
Chen
Qing-Quan
QQ
Li
Zu-De
ZD
Xu
Xiu-Ping
XP
Liu
D000199:Actins / Q000378:metabolism; D000818:Animals; D017209:Apoptosis; D022763:CCAAT-Enhancer-Binding Protein-alpha / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D002251:Carbon Tetrachloride; D020169:Caspases / Q000235:genetics / Q000378:metabolism; D002478:Cells, Cultured; D003094:Collagen / Q000378:metabolism; D053938:DNA Fragmentation; D005109:Extracellular Matrix / Q000378:metabolism; D015870:Gene Expression; D055166:Hepatic Stellate Cells / Q000378:metabolism / Q000502:physiology*; D022781:Hepatocytes / Q000378:metabolism / Q000502:physiology*; D006909:Hydroxyproline / Q000378:metabolism; D008103:Liver Cirrhosis / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D051381:Rats; D011994:Recombinant Proteins / Q000096:biosynthesis / Q000235:genetics; D005723:gamma-Glutamyltransferase / Q000378:metabolism
D000199:Actins; D022763:CCAAT-Enhancer-Binding Protein-alpha; D002251:Carbon Tetrachloride; D020169:Caspases; D003094:Collagen; D006909:Hydroxyproline; D011994:Recombinant Proteins; D005723:gamma-Glutamyltransferase; C498862:Acta2 protein, rat