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ABSTRACT: Activation of hepatic stellate cells (HSC), a resident pericytic cell in liver, into a proliferative and fibrogenic cell type, is the principal event underlying hepatic fibrosis following injury. Release of lipid droplets (LD) containing retinyl esters and triglyceride is a defining feature of HSC activation, yet the basis for this release has remained mysterious. Here we offer a surprising discovery that autophagy is the missing link underlying LD release, by stimulating metabolism of their contents to provide the energy vital to fuel HSC activation. By specifically inhibiting the autophagic pathway in activated HSC, LD release is impaired and cellular ATP levels are decreased. Moreover, animals with HSC-specific deletion of Atg7 display attenuated activation following liver injury, leading to reduced fibrosis in vivo. We further demonstrate that fibrogenic cells from other organs, including kidney and lung, also rely on autophagy as a core pathway driving the scarring response. Our results provide a novel framework for understanding pathways underlying fibrogenic cell responses to tissue injury.
Autophagy 05/2012; 8(5):849-50. · 7.45 Impact Factor
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ABSTRACT: Hepatocellular carcinoma (HCC) is a rising worldwide cause of cancer mortality, making the elucidation of its underlying mechanisms an urgent priority. The liver is unique in its response to injury, simultaneously undergoing regeneration and fibrosis. HCC occurs in the context of these two divergent responses, leading to distinctive pathways of carcinogenesis. In this review we highlight pathways of liver tumorigenesis that depend on, or are enhanced by, fibrosis. Activated hepatic stellate cells drive fibrogenesis, changing the composition of the extracellular matrix. Matrix quantity and stiffness also increase, providing a reservoir for bound growth factors. In addition to promoting angiogenesis, these factors may enhance the survival of both preneoplastic hepatocytes and activated hepatic stellate cells. Fibrotic changes also modulate the activity of inflammatory cells in the liver, reducing the activity of natural killer and natural killer T cells that normally contribute to tumor surveillance. These pathways synergize with inflammatory signals, including telomerase reactivation and reactive oxygen species release, ultimately resulting in cancer. Clarifying fibrosis-dependent tumorigenic mechanisms will help rationalize antifibrotic therapies as a strategy to prevent and treat HCC.
Hepatology 03/2012; 56(2):769-75. · 11.66 Impact Factor
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Anja Lachenmayer,
Sara Toffanin,
Laia Cabellos,
Clara Alsinet,
Yujin Hoshida,
Augusto Villanueva,
Beatriz Minguez,
Hung-Wen Tsai,
Stephen C Ward,
Swan Thung, Scott L Friedman,
Josep M Llovet
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ABSTRACT: Hepatocellular carcinoma (HCC) is a heterogeneous cancer in which sorafenib is the only approved systemic therapy. Histone deacetylases (HDAC) are commonly dysregulated in cancer and therefore represent promising targets for therapies, however their role in HCC pathogenesis is still unknown. We analyzed the expression of 11 HDACs in human HCCs and assessed the efficacy of the pan-HDAC inhibitor panobinostat alone and in combination with sorafenib in preclinical models of liver cancer.
Gene expression and copy number changes were analyzed in a cohort of 334 human HCCs, while the effects of panobinostat and sorafenib were evaluated in three liver cancer cell lines and a murine xenograft model.
Aberrant HDAC expression was identified and validated in 91 and 243 HCCs, respectively. Upregulation of HDAC3 and HDAC5 mRNAs was significantly correlated with DNA copy number gains. Inhibiting HDACs with panobinostat led to strong anti-tumoral effects in vitro and vivo, enhanced by the addition of sorafenib. Cell viability and proliferation declined, while apoptosis and autophagy increased. Panobinostat increased histone H3 and HSP90 acetylation, downregulated BIRC5 (survivin) and upregulated CDH1. Combination therapy with panobinostat and sorafenib significantly decreased vessel density, and most significantly decreased tumor volume and increased survival in HCC xenografts.
Aberrant expression of several HDACs and copy number gains of HDAC3 and HDAC5 occur in HCC. Treatment with panobinostat combined with sorafenib demonstrated the highest preclinical efficacy in HCC models, providing the rationale for clinical studies with this novel combination.
Journal of Hepatology 02/2012; 56(6):1343-50. · 9.26 Impact Factor
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ABSTRACT: 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.
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.
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.
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.
Gastroenterology 01/2012; 142(4):938-46. · 11.68 Impact Factor
