Changes in microRNAs associated with hepatic stellate cell activation status identify signaling pathways

Activation of hepatic stellate cells (HSCs), which is regulated by multiple signal transduction pathways, is the key event in liver fibrosis. Moreover, members of these pathways are important targets for microRNAs (miRNAs). To better understand the critical pathways of HSC activation, we performed comprehensive comparative bioinformatics analysis of microarrays of quiescent and activated HSCs. Changes in miRNAs associated with HSC activation status revealed that 13 pathways were upregulated and 22 pathways were downregulated by miRNA. Furthermore, mitochondrial integrity, based on highly upregulated Bcl‐2 and downregulated caspase‐9, was confirmed in HSCs and fibrotic livers by immnofluorescence assay, quantitative RT‐PCR, and western blot analysis. These findings provide in vitro and in vivo evidence that the mitochondrial pathway of apoptosis plays a significant role in the progression of liver fibrogenesis via HSC activation.

[1]  Bo Liu,et al.  miR-15b and miR-16 are implicated in activation of the rat hepatic stellate cell: An essential role for apoptosis. , 2009, Journal of hepatology.

[2]  J. Armendáriz-Borunda,et al.  Adenoviral delivery of dominant‐negative transforming growth factor β type II receptor up‐regulates transcriptional repressor SKI‐like oncogene, decreases matrix metalloproteinase 2 in hepatic stellate cell and prevents liver fibrosis in rats , 2009, The journal of gene medicine.

[3]  S. Friedman,et al.  PTK787/ZK22258 attenuates stellate cell activation and hepatic fibrosis in vivo by inhibiting VEGF signaling , 2009, Laboratory Investigation.

[4]  S. Dooley,et al.  Hepatocyte-specific Smad7 expression attenuates TGF-beta-mediated fibrogenesis and protects against liver damage. , 2008, Gastroenterology.

[5]  Amitava Das,et al.  Nitric oxide promotes caspase‐independent hepatic stellate cell apoptosis through the generation of reactive oxygen species , 2008, Hepatology.

[6]  H. Tsukamoto,et al.  Wnt antagonism inhibits hepatic stellate cell activation and liver fibrosis. , 2008, American journal of physiology. Gastrointestinal and liver physiology.

[7]  D. Chitwood,et al.  Target mimics modulate miRNAs , 2007, Nature Genetics.

[8]  G. Gwak,et al.  Wnt signaling enhances the activation and survival of human hepatic stellate cells , 2007, FEBS Letters.

[9]  F. Marra,et al.  Proangiogenic cytokines as hypoxia-dependent factors stimulating migration of human hepatic stellate cells. , 2007, The American journal of pathology.

[10]  Christopher J. Parsons,et al.  Gene expression profile of quiescent and activated rat hepatic stellate cells implicates Wnt signaling pathway in activation. , 2006, Journal of hepatology.

[11]  D. Schuppan,et al.  Halofuginone Induces Matrix Metalloproteinases in Rat Hepatic Stellate Cells via Activation of p38 and NFκB* , 2006, Journal of Biological Chemistry.

[12]  R Weiskirchen,et al.  Modern pathogenetic concepts of liver fibrosis suggest stellate cells and TGF-β as major players and therapeutic targets , 2006, Journal of cellular and molecular medicine.

[13]  A. Nègre-Salvayre,et al.  The grape-derived polyphenol resveratrol differentially affects epidermal and platelet-derived growth factor signaling in human liver myofibroblasts. , 2006, The international journal of biochemistry & cell biology.

[14]  Tao Cai,et al.  Automated genome annotation and pathway identification using the KEGG Orthology (KO) as a controlled vocabulary , 2005, Bioinform..

[15]  S. Osada,et al.  Magnetic Resonance Imaging and Expression of Vascular Endothelial Growth Factor in Hepatocellular Nodules in Cirrhosis and Hepatocellular Carcinomas , 2005, Topics in magnetic resonance imaging : TMRI.

[16]  J. Westwick,et al.  SMAD and p38 MAPK Signaling Pathways Independently Regulate α1(I) Collagen Gene Expression in Unstimulated and Transforming Growth Factor-β-stimulated Hepatic Stellate Cells* , 2005, Journal of Biological Chemistry.

[17]  S. Friedman,et al.  Mechanisms of Disease: mechanisms of hepatic fibrosis and therapeutic implications , 2004, Nature Clinical Practice Gastroenterology &Hepatology.

[18]  F. Anania,et al.  Leptin as a novel profibrogenic cytokine in hepatic stellate cells: mitogenesis and inhibition of apoptosis mediated by extracellular regulated kinase (Erk) and Akt phosphorylation , 2004, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[19]  V. Ambros.  The functions of animal microRNAs , 2004, Nature.

[20]  C. Croce,et al.  An oligonucleotide microchip for genome-wide microRNA profiling in human and mouse tissues. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[21]  Susumu Goto,et al.  The KEGG resource for deciphering the genome , 2004, Nucleic Acids Res..

[22]  Brad T. Sherman,et al.  DAVID: Database for Annotation, Visualization, and Integrated Discovery , 2003, Genome Biology.

[23]  D. Brenner,et al.  Liver fibrosis: signals leading to the amplification of the fibrogenic hepatic stellate cell. , 2003, Frontiers in bioscience : a journal and virtual library.

[24]  Thomas D. Schmittgen,et al.  Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method. , 2001, Methods.

[25]  J. Iredale.  Hepatic Stellate Cell Behavior during Resolution of Liver Injury , 2001, Seminars in liver disease.

[26]  V. Desmet,et al.  Human and rat hepatic stellate cells express neurotrophins and neurotrophin receptors. , 2001, Hepatology.

[27]  Yun Wang,et al.  Hypoxic stimulation of vascular endothelial growth factor expression in activated rat hepatic stellate cells , 2000, Hepatology.

[28]  D. Brenner,et al.  New aspects of hepatic fibrosis. , 2000, Journal of hepatology.

[29]  T. Roskams,et al.  Synaptophysin: A novel marker for human and rat hepatic stellate cells. , 1999, The American journal of pathology.

[30]  K. Ishak,et al.  Histological grading and staging of chronic hepatitis. , 1995 .

[31]  S. Friedman,et al.  Isolation and culture of hepatic lipocytes, Kupffer cells, and sinusoidal endothelial cells by density gradient centrifugation with Stractan. , 1987, Analytical biochemistry.

[32]  J. Doering,et al.  DNA methylation patterns in the 5S DNAs of Xenopus laevis. , 1983, Nucleic acids research.