Regulation of hepatic stellate cell activation and growth by transcription factor myocyte enhancer factor 2.
OBJECTIVE
Hepatic stellate cells (HSCs) undergo activation during the development of liver fibrosis. Transcriptional regulation plays a key role in this process. We studied the role of transcription factor myocyte enhancer factor 2 (MEF2) during HSC activation.


METHODS
Culture of HSCs isolated from rat liver on plastic dishes and HSC-T6 on a basement membrane-like matrix were used as models of HSC activation and deactivation, respectively. The expression and activity of MEF2 were correlated with HSC activation. The roles of MEF2 during HSC activation were assessed in vitro and in vivo by animal models of fibrosis.


RESULTS
Early induction of MEF2 messenger RNA and protein accompanied culture-induced HSC activation. This was associated with enhanced MEF2 DNA binding and transactivation activity. p38 mitogen-activated protein kinase but not extracellular signal-regulated kinase pathway was required for increased MEF2 activity during HSC activation. Increased MEF2 protein also correlated with fibrosis in vivo. Reversal of HSC activation was paralleled by a marked decrease in MEF2 protein and activity. Functionally, enhancing MEF2 significantly increased the expression of alpha-smooth muscle actin (alpha-SMA), activated collagen I promoter activity, and stimulated HSC proliferation. MEF2 interference RNA significantly inhibited expression of alpha-SMA, collagen alpha1(I), and proliferating cell nuclear antigen.


CONCLUSIONS
The studies provide the first evidence for the presence of MEF2 in the liver and show that MEF2 regulates multiple aspects of HSC activation. These studies show a novel role of MEF2 as a key nuclear mediator that may participate in the pathologic process of liver fibrogenesis in vivo.
Wang
Xuemin
X
Liver Research Center, Department of Medicine, Rhode Island Hospital and Brown University School of Medicine, Providence 02903, USA.
Tang
Xiaoli
X
Gong
Xiaoming
X
Albanis
Efsevia
E
Friedman
Scott L
SL
Mao
Zixu
Z
D000199:Actins / Q000235:genetics; D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins; D002453:Cell Cycle; D002455:Cell Division; D024042:Collagen Type I / Q000235:genetics; D004268:DNA-Binding Proteins / Q000502:physiology*; D008099:Liver / Q000166:cytology* / Q000378:metabolism; D008103:Liver Cirrhosis / Q000209:etiology*; D064326:MEF2 Transcription Factors; D008297:Male; D020928:Mitogen-Activated Protein Kinases / Q000502:physiology; D018006:Myogenic Regulatory Factors; D011401:Promoter Regions, Genetic; D051381:Rats; D017207:Rats, Sprague-Dawley; D014157:Transcription Factors / Q000502:physiology*; D014158:Transcription, Genetic; D048051:p38 Mitogen-Activated Protein Kinases
D000199:Actins; D051792:Basic Helix-Loop-Helix Proteins; D024042:Collagen Type I; D004268:DNA-Binding Proteins; D064326:MEF2 Transcription Factors; D020928:Mitogen-Activated Protein Kinases; D018006:Myogenic Regulatory Factors; D014157:Transcription Factors; D048051:p38 Mitogen-Activated Protein Kinases