Abstract
Fas/Fas ligand (FasL)-mediated cell apoptosis involves a variety of physiological and pathological processes including chronic hepatic diseases, and hepatocytes apoptosis contributes to the development of liver fibrosis following various causes. However, the mechanism of the Fas/FasL signaling and hepatocytes apoptosis in liver fibrogenesis remains unclear. The Fas/FasL signaling and hepatocytes apoptosis in liver samples from both human sections and mouse models were investigated. NF-κBp65 wild-type mice (p65f/f), hepatocytes specific NF-κBp65 deletion mice (p65Δhepa), p53-upregulated modulator of apoptosis (PUMA) wild-type (PUMA-WT) and PUMA knockout (PUMA-KO) littermate models, and primary hepatic stellate cells (HSCs) were also used. The mechanism underlying Fas/FasL-regulated hepatocytes apoptosis to drive HSCs activation in fibrosis was further analyzed. We found Fas/FasL promoted PUMA-mediated hepatocytes apoptosis via regulating autophagy signaling and NF-κBp65 phosphorylation, while inhibition of autophagy or PUMA deficiency attenuated Fas/FasL-modulated hepatocytes apoptosis and liver fibrosis. Furthermore, NF-κBp65 in hepatocytes repressed PUMA-mediated hepatocytes apoptosis via regulating the Bcl-2 family, while NF-κBp65 deficiency in hepatocytes promoted PUMA-mediated hepatocytes apoptosis and enhanced apoptosis-linked inflammatory response, which contributed to the activation of HSCs and liver fibrogenesis. These results suggest that Fas/FasL contributes to NF-κBp65/PUMA-modulated hepatocytes apoptosis via autophagy to enhance liver fibrogenesis, and this network could be a potential therapeutic target for liver fibrosis.
Highlights
Liver fibrosis represents one of the major consequences of morbidity and mortality worldwide[1,2], and the activation of hepatic stellate cells (HSCs), which is regulated by multiple cell populations or soluble mediators, is the major source of extracellular matrix substances (ECM)[3,4,5]
Fas/Fas ligand (FasL)-mediated apoptosis involved in liver fibrogenesis To evaluate the role of Fas/FasL in liver fibrosis, liver specimens from healthy volunteers and liver fibrosis patients were analyzed
We found that CCl4 injection-induced prominent liver fibrosis in mice as shown by α-SMA and COL-I staining, which was accompanied with obvious apoptosis and Fas/FasL upregulation (Fig. 1a, b), and western blotting further represented that the levels of Fas, FasL, α-SMA, COL-I, COLIV, and cleaved caspase-3 were enhanced in the fibrotic sections (Fig. 1c, d)
Summary
Liver fibrosis represents one of the major consequences of morbidity and mortality worldwide[1,2], and the activation of hepatic stellate cells (HSCs), which is regulated by multiple cell populations or soluble mediators, is the major source of extracellular matrix substances (ECM)[3,4,5]. Hepatocytes are the major parenchymal cells of the liver and essential for maintaining the function and Official journal of the Cell Death Differentiation Association. Nuclear factor-κB (NF-κB), as a ubiquitous and inducible transcription factor responsible for mediating the expression of a large number of genes involved in differentiation, apoptosis, and proliferation[22], and NF-κBp65, as the main functional element, involves in various physiological and pathological events and influences the survival of hepatocytes and activation of HSCs23. Activation of NF-κB in nonparenchymal cells promotes inflammation, fibrosis, and hepatocarcinogenesis in the liver, whereas suppression of NF-κB in parenchymal cells enhances hepatocarcinogenesis in some cases and retards hepatocarcinogenesis in others[10,24]. While decreased or absent NF-κB activity in hepatocytes might lead to subsequent fibrosis by regulating hepatocytes injury and the primary trigger of fibrogenic responses in liver[23,24,25,26]
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