Autophagy Releases Lipid That Promotes Fibrogenesis by Activated Hepatic Stellate Cells in Mice and in Human Tissues

By V. Hernández-Gea, Z. Ghiassi-Nejad, R. Rozenfeld, R. Gordon, M. Fiel, Zhenyu Yue, M. Czaja, S. Friedman. Gastroenterology, 2012

621 citations recorded by the source corpus.

BACKGROUND & AIMS 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, Atg7F/F, and Atg7F/F-GFAP-Cre mice, as well as the mouse stellate cell line JS1. Fibrosis was induced in mice using CCl4 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 CCl4 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.

Subfields: Epidemiology, Hepatology

View Paper: https://www.semanticscholar.org/paper/afacd5c979135625169d53aa9ac72b20ad57c58a

How researchers see this paper

The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

In Epidemiology

1. L. Hammerich
2. Y. Saiman
3. J. Puche
4. F. Tacke
5. S. Friedman
6. G. Svegliati-Baroni
7. F. Marra
8. M. Pinzani

In Hepatology

1. L. Hammerich
2. Y. Saiman
3. J. Puche
4. F. Tacke
5. S. Friedman
6. G. Svegliati-Baroni
7. F. Marra
8. M. Pinzani

Citations in the corpus

• Hepatic inflammatory responses in liver fibrosis (2023, positive): “Autophagy provides energy and nutrients critical for HSC activation through the breakdown of cellular components and organelles 155 ; abrogation of autophagy in mouse HSCs prevents liver fibrogenesis 172 .”
• Therapy for Fibrotic Diseases: Nearing the Starting Line (2013, background): “This highly conserved pathway is induced during mesenchymal cell activation in tissue injury to maintain energy homeostasis in the face of the increased metabolic demands of proliferation, fibrogenesis, and contractility (51).”
• Lipotoxicity and the gut-liver axis in NASH pathogenesis. (2018, background): “Interestingly, while autophagy is in general protective against steatosis in hepatocytes, its activation favors activation of hepatic stellate cells and fibrogenesis [56].”
• Hepatic Stellate Cells and Liver Fibrosis (2013, positive): “The presence of active lysosomes in stellate cell cytoplasm described for decades (33, 129) is now recognized to indicate a high capacity for the cells to undergo autophagy during cellular activation (104, 105).”