FIG. 3.

TGF-β mediates apoptosis of hepatocytes via NOX4 upregulation. After various kinds of liver injury, including alcohol, HCV, and toxic bile acids, ROS is produced via NOXs in hepatocytes, some hepatocytes undergo apoptosis/necrosis, and KCs get activated, releasing proinflammatory and profibrogenic cytokines such as TGF-β. TGF-β binds to and activates TGF-β receptor (TGF-βR I and II), which is accompanied by phosphorylation of Smad2 and Smad3 that are then complexed with Smad4. Then, activated Smad complexes enter the nucleus and initiate the transcription of TGF-β target genes, including NOX4. NOX4-generated H₂O₂ down-regulates Bcl-X_L, a Bcl-2 family of pro-survival protein, resulting in mitochondrial permeability transition in mitochondria followed by cytochrome C release, caspase 3 activation, and apoptosis of hepatocytes. However, EGF binds to EGF receptor, which, in turn, activates MEK/ERK and PI3K/Akt and blocks TGF-β-induced NOX4 upregulation and hepatocytes cell death. EGF, epidermal growth factor; ERK, extracellular signal-regulated kinase; H₂O₂, hydrogen peroxide; HCV, hepatitis C virus. To see this illustration in color, the reader is referred to the web version of this article at www.liebertpub.com/ars