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

Abstract

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.

Naringin in Ganshuang Granule suppresses activation of hepatic stellate cells for anti‐fibrosis effect by inhibition of mammalian target of rapamycin

“…Hernández‐Gea et al . found that inhibition of autophagic function in primary mouse HSCs and mice following reduced fibrogenesis and matrix accumulation, which suggested autophagy promoted HSCs activation 21. Similar to previous study 18, we found that naringin induced autophagic activity in HSCs.…”

MicroRNA‐30a ameliorates hepatic fibrosis by inhibiting Beclin1‐mediated autophagy

“…LDs are characteristic of resident HSCs and their presence and induction suppress HSCs activation 33, 34. Autophagy contributes to the intracellular catabolism of lipids in HSCs 8. Our data revealed an increased number of LDs in LX‐2 cells treated with miR‐30a mimics (Fig.…”

Cellular and molecular mechanisms in liver fibrogenesis

“…Data relating autophagy to liver fibrogenesis first emerged independently by two different groups that showed evidence for an increase of autophagy in activated HSC [98,99], both suggesting that autophagy has a first role in the loss of perinuclear lipid droplets (containg retinyl esters) that accompanies trans-differentiation of quiescent HSC towards the activated phenotype. In a first study autophagy was detected during in vitro activation of primary mouse HSCs by investigating typical autophagyrelated markers, including LC3.…”