Hepatitis C Virus Infection and Hepatic Stellate Cell Activation Downregulate miR-29: miR-29 Overexpression Reduces Hepatitis C Viral Abundance in Culture

• Published in: The Journal of infectious diseases Vol. 203; no. 12; pp. 1753 - 1762
• Main Authors: Bandyopadhyay, Sarmistha, Friedman, Robin C., Marquez, Rebecca T., Keck, Kathy, Kong, Benjamin, Icardi, Michael S., Brown, Kyle E., Burge, Christopher B., Schmidt, Warren N., Wang, Yulei, McCaffrey, Anton P.
• Format: Journal Article
• Language: English
• Published: Oxford Oxford University Press 15-06-2011
• Subjects: Algorithms; Biological and medical sciences; Collagen - biosynthesis; Down regulation; Fibrosis; Fundamental and applied biological sciences. Psychology; Hepacivirus - genetics; Hepacivirus - metabolism; Hepatic stellate cells; Hepatic Stellate Cells - metabolism; Hepatitis; Hepatitis C virus; Hepatitis C, Chronic - pathology; Hepatocytes; Hepatocytes - metabolism; Human viral diseases; Humans; Infections; Infectious diseases; Liver; Liver - pathology; Major and Brief Reports; Medical sciences; Messenger RNA; Microbiology; MicroRNA; MicroRNAs - metabolism; Reverse Transcriptase Polymerase Chain Reaction; RNA, Viral - analysis; Viral diseases; Viral hepatitis; Viruses; Infection; Digestive diseases; Hepatic disease; Viral disease; Viral hepatitis C
• ISSN: 0022-1899; 1537-6613
• DOI: 10.1093/infdis/jir186

Background. Chronic hepatitis C virus (HCV)-induced liver fibrosis involves upregulation of transforming growth factor (TGF)-ß and subsequent hepatic stellate cell (HSC) activation. MicroRNAs (miRNAs) regulate HCV infection and HSC activation. Methods. TaqMan miRNA profiling identified 12 miRNA families differentially expressed between chronically HCV-infected human livers and uninfected controls. To identify pathways affected by miRNAs, we developed a new algorithm (pathway analysis of conserved targets), based on the probability of conserved targeting. Results. This analysis suggested a role for miR-29 during HCV infection. Of interest, miR-29 was downregulated in most HCV-infected patients. miR-29 regulates expression of extracellular matrix proteins. In culture, HCV infection downregulated miR-29, and miR-29 overexpression reduced HCV RNA abundance. miR-29 also appears to play a role in HSCs. Hepatocytes and HSCs contribute similar amounts of miR-29 to whole liver. Both activation of primary HSCs and TGF-ß treatment of immortalized HSCs downregulated miR-29. miR-29 overexpression in LX-2 cells decreased collagen expression and modestly decreased proliferation. miR-29 downregulation by HCV may derepress extracellular matrix synthesis during HSC activation. Conclusions. HCV infection downregulates miR-29 in hepatocytes and may potentiate collagen synthesis by reducing miR-29 levels in activated HSCs. Treatment with miR-29 mimics in vivo might inhibit HCV while reducing fibrosis.