title: Autophagy releases lipid that promotes fibrogenesis by activated hepatic stellate cells in mice and in human tissues.
abstract: OBJECTIVE
  The pathogenesis of liver fibrosis involves activation of hepatic stellate cells, which is associated with depletion of intracellular lipid droplets. When hepatocytes undergo autophagy, intracellular lipids are degraded in lysosomes. We investigated whether autophagy also promotes loss of lipids in hepatic stellate cells to provide energy for their activation and extended these findings to other fibrogenic cells.
  
  
  METHODS
  We analyzed hepatic stellate cells from C57BL/6 wild-type, Atg7(F/F), and Atg7(F/F)-GFAP-Cre mice, as well as the mouse stellate cell line JS1. Fibrosis was induced in mice using CCl(4) or thioacetamide (TAA); liver tissues and stellate cells were analyzed. Autophagy was blocked in fibrogenic cells from liver and other tissues using small interfering RNAs against Atg5 or Atg7 and chemical antagonists. Human pulmonary fibroblasts were isolated from samples of lung tissue from patients with idiopathic pulmonary fibrosis or from healthy donors.
  
  
  RESULTS
  In mice, induction of liver injury with CCl(4) or TAA increased levels of autophagy. We also observed features of autophagy in activated stellate cells within injured human liver tissue. Loss of autophagic function in cultured mouse stellate cells and in mice following injury reduced fibrogenesis and matrix accumulation; this effect was partially overcome by providing oleic acid as an energy substrate. Autophagy also regulated expression of fibrogenic genes in embryonic, lung, and renal fibroblasts.
  
  
  CONCLUSIONS
  Autophagy of activated stellate cells is required for hepatic fibrogenesis in mice. Selective reduction of autophagic activity in fibrogenic cells in liver and other tissues might be used to treat patients with fibrotic diseases.
authors.affiliation: Division of Liver Diseases, Department of Medicine, Mount Sinai School of Medicine, New York, New York 10029-6574, USA.
authors.forename: Virginia
authors.initials: V
authors.lastname: Hernández-Gea
authors.forename: Zahra
authors.initials: Z
authors.lastname: Ghiassi-Nejad
authors.forename: Raphael
authors.initials: R
authors.lastname: Rozenfeld
authors.forename: Ronald
authors.initials: R
authors.lastname: Gordon
authors.forename: Maria Isabel
authors.initials: MI
authors.lastname: Fiel
authors.forename: Zhenyu
authors.initials: Z
authors.lastname: Yue
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Czaja
authors.forename: Scott L
authors.initials: SL
authors.lastname: Friedman
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives / Q000494:pharmacology; D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D001343:Autophagy / Q000187:drug effects / Q000235:genetics; D000071187:Autophagy-Related Protein 5; D000071193:Autophagy-Related Protein 7; D002251:Carbon Tetrachloride; D002460:Cell Line; D004734:Energy Metabolism; D004852:Epoxy Compounds / Q000494:pharmacology; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D055166:Hepatic Stellate Cells / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D054990:Idiopathic Pulmonary Fibrosis / Q000378:metabolism / Q000473:pathology; D007668:Kidney / Q000378:metabolism / Q000473:pathology; D050356:Lipid Metabolism / Q000187:drug effects; D008099:Liver / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D008106:Liver Cirrhosis, Experimental / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D008168:Lung / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008869:Microtubule-Associated Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D019301:Oleic Acid / Q000378:metabolism; D034622:RNA Interference; D013853:Thioacetamide
chemical_list: C495773:Atg5 protein, mouse; C502661:Atg7 protein, mouse; D000071187:Autophagy-Related Protein 5; D004852:Epoxy Compounds; D008869:Microtubule-Associated Proteins; D013853:Thioacetamide; D019301:Oleic Acid; C025946:3-methyladenine; D000255:Adenosine Triphosphate; D002251:Carbon Tetrachloride; D000071193:Autophagy-Related Protein 7; D000225:Adenine; C054207:etomoxir